Prodrugs of diphenyl ox-indol-2-one compounds

ABSTRACT

The present application discloses prodrugs of substituted 3,3-diphenyl-1,3-dihydro-indol-2-one compounds having the general formula (I). The 4-position of the phenyl moieties and the N-position of the indole represent useful handles for the introduction of particular prodrug groups, in particular those comprising an amino acid moiety. The prodrug compounds are believed to be useful for the treatment of cancer in a mammal, possibly in combination with one or more other chemotherapeutic agents. The application also discloses the compounds for use in a method of treating a mammal suffering from or being susceptible to cancer

FIELD OF THE INVENTION

The present invention relates to novel prodrugs of substituted3,3-diphenyl-1,3-dihydro-indol-2-one compounds.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 1,624,675 describes O—O-diacyl derivatives ofdiphenolisatine and that these compounds possess laxative properties.

US 2004/0242563 A1 discloses substituted diphenyl indanone, indane andindole compounds and analogues thereof useful for the treatment orprevention of diseases characterized by abnormal cell proliferation.

WO 05/07107 A1 discloses diphenyl ox-indol-2-one compounds and their usein the treatment of cancer. It is generally suggested that the compoundsmay be present as prodrugs.

However, there is still a need for improved prodrugs of diphenylox-indol-2-one-type compounds.

BRIEF DESCRIPTION OF THE INVENTION

Following further developments within the field of diphenylox-indol-2-one compounds, the present inventors have now found that the4-position of the phenyl moieties and the N-position of the indolerepresent very useful handles for the introduction of prodrug groups andthat particular prodrug groups, in particular those comprising an aminoacid moiety, are particularly promising.

Hence, the present invention provides compounds of the general formulae(I) and (Ia) and (Ib), cf. claims 1, 25, 28 and 29.

The present invention further provides a pharmaceutical composition, cf.claim 35, the utilization of compounds of the general formulae (I) and(Ia) and (Ib) in medicine, cf. claims 37, 38 and 40.

DETAILED DESCRIPTION OF THE INVENTION

The Compounds of the General Formula (I)

The present invention i.a. relates to particular prodrug compounds whichare useful for the treatment of cancer in a mammal.

The useful prodrug compounds have the general formula (I), namely

wherein

each of X¹ and X² independently represents a prodrug group of any of thetypes (i)-(vi)

(i) —O—C(═O)—Z, wherein Z is selected from substituted C₁₋₆-alkyl and—CH(R⁶)N(R⁷)R⁸;

(ii) —O—C(═O)—O—Y, wherein Y is selected from optionally substitutedC₁₋₆-alkyl, or —O—Y represents

-   -   wherein A is selected from optionally substituted        C₁₋₆-alkylidene and optionally substituted benzylidene,    -   B is selected from a single bond, —O— and —S—,    -   R⁵ is selected from hydrogen, optionally substituted C₁₋₆-alkyl,        optionally substituted C₁₋₆-alkoxy, optionally substituted        C₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl,        mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino,        C₁₋₆-alkylcarbonylamino, mono- and di(C₁₋₆-alkyl)amino, aryl,        aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy,        heterocyclylcarbonyl, heterocyclylamino, heteroaryl,        heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where        any C₁₋₆-alkyl as an amino substituent is optionally substituted        with hydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino,        carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or        halogen(s), and wherein any aryl, heterocyclyl and heteroaryl        may be optionally substituted; or —C(═O)—B—R⁵ in prodrug        groups (iii) and (vii) may represent an optionally N-substituted        amino acid;    -   R⁶ is selected from hydrogen, optionally substituted C₁₋₆-alkyl,        optionally substituted C₂₋₆-alkenyl, aryl, heterocyclyl, and        heteroaryl, wherein any aryl, heterocyclyl and heteroaryl may be        optionally substituted;    -   R⁷ and R⁸ are independently selected from hydrogen, optionally        substituted C₁₋₆-alkyl, hydroxy, optionally substituted        C₁₋₆-alkoxy, optionally substituted C₁₋₆-alkoxycarbonyl,        optionally substituted C₁₋₆-alkylcarbonyl, formyl, mono- and        di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino,        mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl,        C₁₋₆-alkylsulphinyl, aryl, aryloxy, arylcarbonyl, arylamino,        heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl,        heterocyclylamino, heteroaryl, heteroaryloxy,        heteroarylcarbonyl, and heteroarylamino; where any C₁₋₆-alkyl as        an amino substituent is optionally substituted with hydroxy,        C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,        C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s),        and wherein any aryl, heterocyclyl and heteroaryl may be        optionally substituted;    -   or R⁷ and R⁸ together with the nitrogen atoms to which they are        attached form a heterocyclic ring; and    -   R⁹ is selected from hydrogen, hydroxy, optionally substituted        C₁₋₆-alkyl, optionally substituted C₁₋₆-alkoxy, and optionally        substituted C₂₋₆-alkenyloxy;    -   R¹⁰ is selected from hydroxy, optionally substituted C₁₋₆-alkyl,        optionally substituted C₁₋₆-alkoxy, optionally substituted        C₂₋₆-alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy,        wherein any aryl, heterocyclyl and heteroaryl may be optionally        substituted;

provided that R⁹ and R¹⁰ are not both selected from hydroxy andC₁₋₆-alkoxy;

or is selected from hydrogen, hydroxy, optionally substituted C₁₋₆alkoxy, optionally substituted C₁₋₆alkyl, optionally substitutedC₂₋₆alkenyl, carboxy, optionally substituted C₁₋₆-alkoxycarbonyl,C₁₋₆-alkylcarbonyloxy, optionally substituted C₁₋₆ alkylcarbonyl,formyl, amino, mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylsulphonylamino, mono- and di(C₁₋₆-alkyl)aminocarbonylamino,carbamoyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, mercapto, optionallysubstituted C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, cyano, halogen, aryl, aryloxy, arylamino,arylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocycylcarbonyl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl,where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxyl, C₁₋₆-alkoxy, amino, mono and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonyl-amino, C₁₋₆alkylaminocarbonyl or halogen(s)and wherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted;

R^(N) represents a prodrug group of any of the types (vii)-(viii)

-   -   wherein A, B and R⁵ are as defined above for prodrug group        (iii);

or is selected from hydrogen, optionally substituted C₁₋₆-alkyl,hydroxy, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino,mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, andC₁₋₆-alkylsulphinyl; where any C₁₋₆-alkyl as an amino substituent isoptionally substituted with hydroxy, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s);

with the proviso that the compound comprises at least one of the prodruggroups (i)-(viii);

V¹, V², V³, and V⁴ independently are selected from a carbon atom, anon-quaternary nitrogen atom, an oxygen atom, and a sulfur atom, andwhere V⁴ further may be selected from a bond, so that —V¹—V²—V³—V⁴—together with the atoms to which V¹ and V⁴ are attached form an aromaticor heteroaromatic ring;

R¹, R², R³, and R⁴, when attached to a carbon atom, independently areselected from hydrogen, optionally substituted C₁₋₆-alkyl, optionallysubstituted C₂₋₆-alkenyl, hydroxy, optionally substituted C₁₋₆-alkoxy,optionally substituted C₂₋₆-alkenyloxy, carboxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl,optionally substituted C₁₋₆-alkylcarbonyloxy, formyl, amino, mono- anddi(C₁₋₆-alkyl)amino, carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino, cyano, carbamido,mono- and di(C₁₋₆-alkyl)aminocarbonylamino, C₁₋₆-alkanoyloxy,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl,heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heteroaryl,heteroaryloxy, heteroarylamino, heteroarylcarbonyl, and halogen, whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s), andwherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted;

R¹, R², R³, and R⁴, when attached to a nitrogen atom, independently areselected from hydrogen, optionally substituted C₁₋₆-alkyl, hydroxy,optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino,mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl,aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy,heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy,heteroarylcarbonyl, and heteroarylamino; where any C₁₋₆-alkyl as anamino substituent is optionally substituted with hydroxy, C₁₋₆-alkoxy,amino, mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted;

or R¹ and R² together with the carbon atoms to which they are attachedform a ring, e.g. an aromatic ring, a carbocyclic ring, a heterocyclicring or a heteroaromatic ring, in particular an aromatic ring, aheterocyclic ring or a heteroaromatic ring;

with the proviso that when each of V¹, V², V³ and V⁴ represents a carbonatom, then R^(N), R¹, R², R³, and R⁴ are not all hydrogen; and

pharmaceutically acceptable salts thereof.

Definitions

In the present context, the term “C₁₋₆-alkyl” is intended to mean alinear, cyclic or branched hydrocarbon group having 1 to 6 carbon atoms,such as methyl, ethyl, propyl, iso-propyl, pentyl, cyclopentyl, hexyl,cyclohexyl, and the term “C₁₋₄-alkyl” is intended to cover linear,cyclic or branched hydrocarbon groups having 1 to 4 carbon atoms, e.g.methyl, ethyl, propyl, iso-propyl, cyclopropyl, butyl, iso-butyl,tert-butyl, cyclobutyl.

Similarly, the term “C₂₋₆-alkenyl” is intended to cover linear, cyclicor branched hydrocarbon groups having 2 to 6 carbon atoms and comprisingone unsaturated bond. Examples of alkenyl groups are vinyl, allyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl. Preferredexamples of alkenyl are vinyl, allyl, butenyl, especially allyl.

In the present context, i.e. in connection with the terms “alkyl”,“alkylidene”, “alkoxy”, “alkenyl” and the like, the term “optionallysubstituted” is intended to mean that the group in question may besubstituted one or several times, preferably 1-3 times, with group(s)selected from hydroxy (which when bound to an unsaturated carbon atommay be present in the tautomeric keto form), C₁₋₆-alkoxy (i.e.C₁₋₆-alkyl-oxy), C₂₋₆-alkenyloxy, carboxy, oxo (forming a keto oraldehyde functionality), C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl,formyl, aryl, aryloxy, arylamino, arylcarbonyl, aryloxycarbonyl,arylcarbonyloxy, arylaminocarbonyl, arylcarbonylamino, heteroaryl,heteroaryloxy, heteroarylamino, heteroarylcarbonyl,heteroaryloxycarbonyl, heteroarylcarbonyloxy, heteroarylaminocarbonyl,heteroarylcarbonylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylcarbonyloxy, heterocyclylaminocarbonyl,heterocyclylcarbonylamino, amino, mono- and di(C₁₋₆-alkyl)amino,—N(C₁₋₄-alkyl)₃ ⁺, carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkylcarbonylamino, cyano, guanidino, carbamido,C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkanoyloxy, C₁₋₆-alkyl-sulphonyl,C₁₋₆-alkyl-sulphinyl, C₁₋₆-alkylsulphonyloxy, nitro, C₁₋₆-alkylthio, andhalogen, where any aryl, heteroaryl and heterocyclyl may be substitutedas specifically described below for aryl, heteroaryl and heterocyclyl,and any alkyl, alkoxy, and the like, representing substituents may besubstituted with hydroxy, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s). Typically, the substituents areselected from hydroxy (which when bound to an unsaturated carbon atommay be present in the tautomeric keto form), C₁₋₆-alkoxy (i.e.C₁₋₆-alkyl-oxy), C₂₋₆-alkenyloxy, carboxy, oxo (forming a keto oraldehyde functionality), C₁₋₆-alkylcarbonyl, formyl, aryl, aryloxy,arylamino, arylcarbonyl, heteroaryl, heteroaryloxy, heteroarylamino,heteroarylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocyclylcarbonyl, amino, mono- and di(C₁₋₆-alkyl)amino; carbamoyl,mono- and di(C₁₋₆-alkyl)amino-carbonyl, amino-C₁₋₆-alkyl-aminocarbonyl,mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkylcarbonylamino, guanidino, carbamido,C₁₋₆-alkylsulphonyl-amino, C₁₋₆-alkyl-sulphonyl, C₁₋₆-alkyl-sulphinyl,C₁₋₆-alkylthio, halogen, where any aryl, heteroaryl and heterocyclyl maybe substituted as specifically described below for aryl, heteroaryl andheterocyclyl. In some embodiments, substituents are selected fromhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen.

The term “halogen” includes fluoro, chloro, bromo, and iodo.

In the present context, the term “aryl” is intended to mean a fully orpartially aromatic carbocyclic ring or ring system, such as phenyl,naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl,benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferredexample.

The term “heteroaryl” is intended to mean a fully or partially aromaticcarbocyclic ring or ring system where one or more of the carbon atomshave been replaced with heteroatoms, e.g. nitrogen (═N— or —NH—),sulphur, and/or oxygen atoms. Examples of such heteroaryl groups areoxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,coumaryl, furanyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl,benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl,tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl,benzopyrazolyl, phenoxazonyl. Particularly interesting heteroaryl groupsare benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, furyl, thienyl, quinolyl, triazolyl, tetrazolyl,isoquinolyl, indolyl in particular benzimidazolyl, pyrrolyl, imidazolyl,pyridinyl, pyrimidinyl, furyl, thienyl, quinolyl, tetrazolyl, andisoquinolyl.

The term “heterocyclyl” is intended to mean a non-aromatic carbocyclicring or ring system where one or more of the carbon atoms have beenreplaced with heteroatoms, e.g. nitrogen (═N— or —NH—), sulphur, and/oroxygen atoms. Examples of such heterocyclyl groups (named according tothe rings) are imidazolidine, piperazine, hexahydropyridazine,hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine,azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane,oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, andhexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane,thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane,tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene,tetrahydrothiopyrane, thiepane, dithiane, dithiepane, dioxane,dioxepane, oxathiane, oxathiepane. The most interesting examples aretetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine,hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine,azepane, azocane, azetidine, tropane, oxazinane (morpholine), oxazolane,oxazepane, thiazolane, thiazinane, and thiazepane, in particulartetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine,hexahydropyrimidine, diazepane, pyrrolidine, piperidine, azepane,oxazinane (morpholine), and thiazinane.

In the present context, i.e. in connection with the terms “aryl”,“benzylidene”, “heteroaryl”, “heterocyclyl” and the like (e.g.“aryloxy”, “heterarylcarbonyl”, etc.), the term “optionally substituted”is intended to mean that the group in question may be substituted one orseveral times, preferably 1-5 times, in particular 1-3 times, withgroup(s) selected from hydroxy (which when present in an enol system maybe represented in the tautomeric keto form), C₁₋₆-alkyl, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, oxo (which may be represented in the tautomeric enolform), carboxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl, formyl, aryl,aryl-oxy, arylamino, aryloxycarbonyl, arylcarbonyl, heteroaryl,heteroarylamino, amino, mono- and di(C₁₋₆-alkyl)amino; carbamoyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono-and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkylcarbonylamino, cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy,C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkyl-suphonyl, C₁₋₆-alkyl-sulphinyl,C₁₋₆-alkylsulphonyloxy, nitro, sulphanyl, amino, amino-sulfonyl, mono-and di(C₁₋₆-alkyl)amino-sulfonyl, dihalogen-C₁₋₄-alkyl,trihalogen-C₁₋₄-alkyl, halogen, where aryl and heteroaryl representingsubstituents may be substituted 1-3 times with C₁₋₄-alkyl, C₁₋₄-alkoxy,nitro, cyano, amino or halogen, and any alkyl, alkoxy, and the like,representing substituents may be substituted with hydroxy, C₁₋₆-alkoxy,C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidino. Typically, the substituentsare selected from hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy, oxo (which may berepresented in the tautomeric enol form), carboxy, C₁₋₆-alkylcarbonyl,formyl, amino, mono- and di(C₁₋₆-alkyl)amino; carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkylcarbonylamino, guanidino, carbamido,C₁₋₆-alkyl-sulphonyl-amino, aryl-sulphonyl-amino,heteroaryl-sulphonyl-amino, C₁₋₆-alkyl-suphonyl, C₁₋₆-alkyl-sulphinyl,C₁₋₆-alkylsulphonyloxy, sulphanyl, amino, amino-sulfonyl, mono- anddi(C₁₋₆-alkyl)amino-sulfonyl or halogen, where any alkyl, alkoxy and thelike, representing substituents may be substituted with hydroxy,C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, amino, mono- and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, halogen, C₁₋₆-alkylthio,C₁₋₆-alkyl-sulphonyl-amino, or guanidino. In some embodiments, thesubstituents are selected from C₁₋₆-alkyl, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, sulphanyl, carboxy or halogen, where any alkyl,alkoxy and the like, representing substituents may be substituted withhydroxy, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino, halogen,C₁₋₆-alkylthio, C₁₋₆-alkyl-sulphonyl-amino, or guanidino.

The expression “optionally N-substituted amino acid” refers to an aminoacid moiety wherein the α-nitrogen is represented by —N(R⁷)R⁸, whereinR⁷ and R⁸ are as defined herein. A non-substituted variant is the onewhere R⁷ and R⁸ are both hydrogen.

The term “prodrug” used herein is intended to mean a compound which—uponexposure to physiological conditions—will liberate a derivative saidcompound which then will be able to exhibit the desired biologicalaction.

The term “pharmaceutically acceptable salts” is intended to include acidaddition salts and basic salts. Illustrative examples of acid additionsalts are pharmaceutically acceptable salts formed with non-toxic acids.Exemplary of such organic salts are those with maleic, fumaric, benzoic,ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, and theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline. Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, and nitric acids. Examples of basic salts aresalts where the (remaining) counter ion is selected from alkali metals,such as sodium and potassium, alkaline earth metals, such as calcium,and ammonium ions (⁺N(R)₃R′, where R and R′ independently designatesoptionally substituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl,optionally substituted aryl, or optionally substituted heteroaryl).Pharmaceutically acceptable salts are, e.g., those described inRemington's Pharmaceutical Sciences, 17. Ed. Alfonso R. Gennaro (Ed.),Mack Publishing Company, Easton, Pa., U.S.A., 1985 and more recenteditions and in Encyclopedia of Pharmaceutical Technology. Thus, theterm “an acid addition salt or a basic salt thereof” used herein isintended to comprise such salts. Furthermore, the compounds as well asany intermediates or starting materials may also be present in hydrateform.

Moreover, it should be understood that the compounds may be present asenantiomers or diastereomers, e.g. when X¹ and X² are different. Thepresent invention encompasses each and every of such possibleenantiomers and diastereomers as well as racemates and mixtures enrichedwith respect to one or the possible enantiomers or diastereomers.

Embodiments

It should be understood that the compound of the general formula (I)must include at least one prodrug group of any of the types (i), (ii),(iii), (iv), (v), (vi), (vii) and (viii). The compound may comprise onlyone prodrug group, i.e. one of X¹ and X² is a prodrug group of any ofthe types (i)-(vi), or R^(N) is a prodrug group of any of the types(vii)-(viii). Alternatively, the compound may comprise more than oneprodrug group, e.g. both of X¹ and X² are prodrug group of any of thetypes (i)-(vi), or R^(N) is a prodrug group of any of the types(vii)-(viii) while one of X¹ and X² is a prodrug group of any of thetypes (i)-(vi), or both of X¹ and X² are prodrug group of any of thetypes (i)-(vi) and R^(N) is a prodrug group of any of the types(vii)-(viii).

In the currently most interesting embodiment, at least one of X¹ and X²represents a prodrug group (i) —O—C(═O)—Z, wherein Z is selected fromsubstituted C₁₋₆-alkyl and —CH(R⁶)N(R⁷)R⁸.

In one variant hereof, Z represents a substituted C₁₋₆-alkyl.

In another currently more preferred variant, Z represents—CH(R⁶)—N(R⁷)R⁸.

Typically, R⁶ is selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, aryl, heterocyclyl, andheteroaryl, wherein any aryl, heterocyclyl and heteroaryl may beoptionally substituted, or R⁶ and R⁸ together with the interveningcarbon and nitrogen atoms to which they are attached form a heterocyclicring.

Also typically, R⁷ and R⁸ are independently selected from hydrogen,optionally substituted C₁₋₆-alkyl, hydroxy, optionally substitutedC₁₋₆-alkoxy, optionally substituted C₁₋₆-alkoxycarbonyl, optionallysubstituted C₁₋₆-alkylcarbonyl, formyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aryl,aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy,heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy,heteroarylcarbonyl, and heteroarylamino; where any C₁₋₆-alkyl as anamino substituent is optionally substituted with hydroxy, C₁₋₆-alkoxy,amino, mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted; or R⁷ and R⁸together with the nitrogen atoms to which they are attached form aheterocyclic ring.

Within this variant, however, R⁶ is preferably selected from side chainsof essential amino acids, or R⁶ and R⁸ together with the interveningcarbon and nitrogen atoms to which they are attached form a heterocyclicring. In such instances, R⁶ is preferably selected from hydrogen(representing glycine), methyl(alanine), 2-propyl(valine),2-methyl-1-propyl(leucine), 2-butyl(isoleucine),methylthioethyl(methionine), benzyl(phenylalanine),3-indolylmethyl(tryptophan), hydroxymethyl(serine),1-hydroxyethyl(threonine), mercaptomethyl(cysteine),4-hydroxybenzyl(tyrosine), aminocarbonylmethyl(asparagine),2-aminocarbonylethyl(glutamine), carboxymethyl(aspartic acid),2-carboxyethyl(glutamic acid), 4-amino-1-butyl(lysine),3-guanidino-1-propyl(arginine), and 4-imidazolylmethyl(histidine), or R⁶and R⁸ together with the intervening carbon and nitrogen atoms to whichthey are attached form a pyrrolidine ring (proline).

In another preferred embodiment, at least one of X¹ and X² represents aprodrug group (ii) —O—C(═O)—O—Y, wherein Y is selected from optionallysubstituted C₁₋₆-alkyl, or —O—Y represents

Also preferred are the variants of the above-mentioned embodiment(prodrug groups (i) and (ii)) where R⁷ is hydrogen and R⁸ is selectedfrom hydrogen, optionally substituted C₁₋₆-alkyl, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylsulphonyl,C₁₋₆-alkylsulphinyl, aryl, arylcarbonyl, heterocyclyl, heterocyclyloxy,heteroaryl, and heteroaryloxy; where any C₁₋₆-alkyl as an aminosubstituent is optionally substituted with hydroxy, C₁₋₆-alkoxy, amino,mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted; or R⁷ and R⁸together with the nitrogen atoms to which they are attached form aheterocyclic ring.

In another preferred embodiment, at least one of X¹ and X² represents aprodrug group (iii)

Typically, A is selected from optionally substituted C₁₋₆-alkylidene andoptionally substituted benzylidene; B is selected from a single bond,—O— and —S—; and R⁵ is selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono-and di(C₁₋₆-alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino,heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino,heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino;where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, orhalogen(s), and wherein any aryl, heterocyclyl and heteroaryl may beoptionally substituted; or —C(═O)—B—R⁵ in prodrug group (iii) mayrepresent an optionally N-substituted amino acid.

In one variant, R⁵ is selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono-and di(C₁₋₆-alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino,heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino,heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino;where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, orhalogen(s), and wherein any aryl, heterocyclyl and heteroaryl may beoptionally substituted.

In another currently preferred variant, —C(═O)—B—R⁵ in prodrug group(iii) may represent an optionally N-substituted amino acid, i.e. B is asingle bond and R⁵ represents —CH(R⁶)—N(R⁷)R⁸, wherein R⁶, R⁷ and R⁸ areas defined above for prodrug groups (i) and (ii). In particular, R⁶ ispreferably selected from side chains of essential amino acids, or R⁶ andR⁸ together with the intervening carbon and nitrogen atoms to which theyare attached form a pyrrolidine ring (see the examples above for prodruggroups (i) and (ii)).

In still another embodiment, at least one of X¹ and X² represents aprodrug group of any of the types (iv)-(vi)

Typically, A is selected from optionally substituted C₁₋₆-alkylidene andoptionally substituted benzylidene; R⁹ is selected from hydrogen,hydroxy, optionally substituted C₁₋₆-alkyl, optionally substitutedC₁₋₆-alkoxy, and optionally substituted C₂₋₆-alkenyloxy; and R¹⁰ isselected from hydroxy, optionally substituted C₁₋₆-alkyl, optionallysubstituted C₁₋₆-alkoxy, optionally substituted C₂₋₆-alkenyloxy;aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted; provided thatR⁹ and R¹⁰ are not both selected from hydroxy and C₁₋₆-alkoxy.

Within this embodiment, R⁹ is preferably selected from hydrogen andhydroxy, and R¹⁰ is preferably selected from optionally substitutedC₁₋₆-alkoxy, optionally substituted C₂₋₆-alkenyloxy; aryloxy,heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl andheteroaryl may be optionally substituted. More particular, R⁹ ishydroxy, and R¹⁰ is selected from optionally substituted C₁₋₆-alkoxy,aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted.

In yet another embodiment, R^(N) represents a prodrug group or any ofthe types (vii)-(viii)

Typically, A is selected from optionally substituted C₁₋₆-alkylidene andoptionally substituted benzylidene; B is selected from a single bond,—O—, and —S—; and R⁵ is selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono-and di(C₁₋₆-alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino,heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino,heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino;where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, orhalogen(s), and wherein any aryl, heterocyclyl and heteroaryl may beoptionally substituted; or —C(═O)—B—R⁵ in prodrug group (vii) mayrepresent an optionally N-substituted amino acid.

In a currently preferred variant, —C(═O)—B—R⁵ in prodrug group (vii)represent an optionally N-substituted amino acid, i.e. B is a singlebond and R⁵ represents —CH(R⁶)—N(R⁷)R⁸, wherein R⁶, R⁷ and R⁸ are asdefined above for prodrug groups (i) and (ii). In particular, R⁶ ispreferably selected from side chains of essential amino acids, or R⁶ andR⁸ together with the intervening carbon and nitrogen atoms to which theyare attached form a pyrrolidine ring (see the examples above for prodruggroups (i) and (ii)).

The function of V¹, V², V³, and V⁴ is mainly believed to be of stericalcharacter, i.e. determinative for the orientation of the groups R¹-R⁴.It is, however, also believed that the selection of a heteroatom as oneor more of V¹, V², V³, and V⁴ may create dipole interactions with otherentities and thereby have influence on, e.g., the solubility of thecompounds of the general formula (I).

V¹, V², V³, and V⁴ are independently selected from a carbon atom, anon-quaternary nitrogen atom, an oxygen atom, and a sulfur atom, andwhere V⁴ further may be selected from a bond, so that —V¹—V²—V³—V⁴—together with the atoms to which V¹ and V⁴ are attached form an aromaticor heteroaromatic ring. Particularly useful examples of such aromaticrings and heteroaromatic rings are those selected from a benzene ring, athiophene ring (V¹═S, V²═V³═C(−) and V⁴=bond; V²═S, V¹═V³═C(−) andV⁴=bond; or V³═S, V¹═V²═C(−) and V⁴=bond), a furan ring (V¹═O,V²═V³═C(−) and V⁴=bond; V²═O, V¹═V³═C(−) and V⁴=bond; or V³═O,V¹═V²═C(−) and V⁴=bond), a pyrazole ring (V¹═N(−), V²═N, V³═C(−) andV⁴=bond; V¹═N, V²═N(−), V³═C(−) and V⁴=bond), an imidazole ring(V¹═N(−), V²═C(−), V³═N and V⁴=bond; V¹═N, V²═C(−), V³═N(−) andV⁴=bond), a pyridine ring (V¹═N, V²═V³═V⁴═C(−); V²═N, V¹═V³═V⁴═C(−);V³═N, V¹═V²═V⁴═C(−) and V⁴═N, V¹═V²═V³═C(−)), a pyrimidine ring(V¹═V³═N, V²═V⁴═C(−); V²═V⁴═N, V¹═V³═C(−)), pyrazines (V¹═V⁴═N,V²═V³═C(−)), a pyridazine ring (V¹═V²═N, V³═V⁴═C(−); V²═V³═N,V¹═V⁴═C(−); V³═V⁴═N, V¹═V²═C(−)), a thiazole ring (V¹═N, V²═C(−), V³═S,V⁴=bond; V¹═S, V²═C(−), V³═N, V⁴=bond), and an isothiazole ring (V¹═N,V²═S, V³═C(−), V⁴=bond; V¹═S, V²═N, V³═C(−), V⁴=bond; V¹═C(−), V²═S,V³═N, V⁴=bond; V¹═C(−), V²═N, V³═S, V⁴=bond).

The meaning of V¹, V², V³ and V⁴ for each heteroaromatic ring is merelyspecified for the purpose of illustrating that various orientations ofthe heteroatoms are possible. Furthermore, it should be understood thatthe respective rings carry the substituents R¹, R², R³ and R⁴ (whereapplicable) in accordance with the general formula (I). Thus,specification of “C(−)” and “N(−)” as possible meanings of V¹, V², V³and V⁴ is made for the purpose of describing that the atoms in questioncarry a substituent (which may be hydrogen). Specification of “N” meansthat the respective atoms do not carry an “R” substituent, i.e. thecorresponding “R” substituent is absent.

In one embodiment, —V¹—V²—V³—V⁴— together with the atoms to which V¹ andV⁴ are attached form a ring selected from a benzene ring, a thiophenering, a furan ring, a pyrazole ring, an imidazole ring, a pyridine ring,a pyrimidine ring, pyrazines, and a pyridazine ring, in particular froma benzene ring and a pyridine ring where the nitrogen atom represents V³(see also the Examples). In accordance with the general formula (I), therespective ring (aromatic or heteroaromatic) carries the substituentsR¹-R⁴ (where applicable).

The substituents R¹-R⁴ (where applicable) are believed to be at leastpartly responsible for the biological effect, e.g. the ability of thecompounds to inhibit cell proliferation in cancer cells.

In one embodiment, R¹, R², R³, and R⁴ are, when attached to a carbonatom, independently selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, hydroxy, optionallysubstituted C₁₋₆-alkoxy,optionally substituted C₂₋₆-alkenyloxy, carboxy,optionally substituted C₁₋₆-alkoxycarbonyl, optionally substitutedC₁₋₆-alkylcarbonyl, optionally substituted C₁₋₆-alkylcarbonyloxy,formyl, amino, mono- and di(C₁₋₆-alkyl)amino, carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylsulphonylamino, cyano, carbamido, mono- anddi(C₁₋₆-alkyl)aminocarbonylamino, C₁₋₆-alkanoyloxy, C₁₋₆-alkylsulphonyl,C₁₋₆-alkylsulphinyl, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, and halogen, where any C₁₋₆-alkyl as an aminosubstituent is optionally substituted with hydroxy, C₁₋₆-alkoxy, amino,mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s); and R¹, R², R³, and R⁴ are, whenattached to a nitrogen atom, independently selected from hydrogen,optionally substituted C₁₋₆-alkyl, hydroxy, optionally substitutedC₁₋₆-alkoxy, optionally substituted C₁₋₆-alkoxycarbonyl, optionallysubstituted C₁₋₆-alkylcarbonyl, formyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, and C₁₋₆-alkylsulphinyl; whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s), andwherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted.

More particularly, R¹, R², R³, and R⁴ are independently selected fromhydrogen, halogen, optionally substituted C₁₋₆-alkyl, hydroxy,optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, amino,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylsulphonylamino, mono- and di(C₁₋₆-alkyl)aminosulfonyl, andmono- and di(C₁₋₆-alkyl)amino, where any C₁₋₆-alkyl as an aminosubstituent is optionally substituted with hydroxy, C₁₋₆-alkoxy, amino,mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), such as from hydrogen,optionally substituted C₁₋₆-alkyl, hydroxy, optionally substitutedC₁₋₆-alkoxy, optionally substituted C₁₋₆-alkoxycarbonyl, optionallysubstituted C₁₋₆-alkylcarbonyl, amino, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkyl-carbonylamino, C₁₋₆-alkylsulphonylamino, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, and mono- and di(C₁₋₆-alkyl)amino, whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s).

As an alternative to the above, R¹ and R² may in one embodiment togetherwith the carbon atoms to which they are attached form a heterocyclicring or a heteroaromatic ring; and in another embodiment, R¹ and R² maytogether with the carbon atoms to which they are attached form anaromatic ring or a carbocyclic ring.

Preferably, R¹, R², R³ and R⁴ are not all hydrogen.

In a currently highly preferred embodiment, R¹ and R² are both halogen,in particular, R¹ and R² are both fluoro. In a variant within thisembodiment, R^(N), R³ and R⁴ are all hydrogen.

It is believed that R^(N) may be selected from a wide variety ofsubstituents including the prodrug group (vi). If not being a prodruggroup, R^(N) may advantageous be selected from hydrogen, C₁₋₆-alkyl,amino, and C₁₋₆-alkylcarbonylamino. Most preferred is the variantswherein R^(N) is selected from hydrogen and C₁₋₆-alkyl, in particularfrom hydrogen and methyl, most typical hydrogen.

In one currently preferred variant,

each of V¹, V², V³, and V⁴ represents a carbon atom;

R¹ and R² are both fluoro;

R³ and R⁴ are all hydrogen;

R^(N) is hydrogen;

at least one of X¹ and X² represents a prodrug group (i)—O—C(═O)—CH(R⁶)—N(R⁷)R⁸,

wherein R⁶ is selected from hydrogen(glycine), methyl(alanine),2-propyl(valine), 2-methyl-1-propyl(leucine), 2-butyl(isoleucine),methylthioethyl(methionine), benzyl(phenylalanine),3-indolylmethyl(tryptophan), hydroxymethyl(serine),1-hydroxyethyl(threonine), mercaptomethyl(cysteine),4-hydroxybenzyl(tyrosine), aminocarbonylmethyl(asparagine),2-aminocarbonylethyl(glutamine), carboxymethyl(aspartic acid),2-carboxyethyl(glutamic acid), 4-amino-1-butyl(lysine),3-guanidino-1-propyl(arginine), and 4-imidazolylmethyl(histidine), or R⁶and R⁸ together with the intervening carbon and nitrogen atoms to whichthey are attached form a pyrrolidine ring (proline);

R⁷ is hydrogen and R⁸ is selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₁₋₆-alkoxycarbonyl, optionallysubstituted C₁₋₆-alkylcarbonyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aryl, arylcarbonyl,heterocyclyl, heterocyclyloxy, heteroaryl, and heteroaryloxy; where anyC₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s), andwherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted; or R⁷ and R⁸ together with the nitrogen atoms to which theyare attached form a heterocyclic ring; and

any other of X¹ or X² is selected from hydrogen, hydroxy, optionallysubstituted C₁₋₆ alkoxy, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, carboxy, optionally substitutedC₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy, optionally substitutedC₁₋₆alkylcarbonyl, formyl, amino, mono- and di(C₁₋₆-alkyl)amino,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino, mono- anddi(C₁₋₆-alkyl)aminocarbonylamino, carbamoyl, mono-anddi(C₁₋₆-alkyl)aminocarbonyl, mercapto, optionally substitutedC₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, cyano, halogen, aryl, aryloxy, arylamino,arylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocycylcarbonyl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl,where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxyl, C₁₋₆-alkoxy, amino, mono and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆ alkylaminocarbonyl or halogen(s)and wherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted.

In one particular embodiment, R¹ is selected from hydrogen, halogen,C₁₋₆-alkyl, trifluoromethyl and C₁₋₆-alkoxy, when V¹ is a carbon atom.

In a further embodiment, R² is selected from hydrogen, halogen,optionally substituted aryl, optionally substituted aryloxy, andoptionally substituted heteroaryl, when V² is a carbon atom.

In a still further embodiment, R³ is selected from hydrogen, optionallysubstituted C₁₋₆-alkoxy, halogen, cyano, optionally substituted aryl,optionally substituted aryloxy, optionally substituted heteroaryl,amino, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino, and mono- anddi(C₁₋₆-alkyl)aminosulfonyl, when V³ is a carbon atom.

In an even still further embodiment, R⁴ is hydrogen, when V⁴ is a carbonatom.

The Compounds of General Formula (Ia)

It has been found that the compounds wherein at least one prodrug groupcomprising an amino acid moiety is present represents a particularlyinteresting aspect of the present invention. Hence, the presentinvention also provides a compound of the general formula (Ia)

wherein

at least one of X¹, X² and R^(N) represent a prodrug group comprising anamino acid moiety,

any of X¹ and X² not being a prodrug group independently being selectedfrom hydrogen, hydroxy, optionally substituted C₁₋₆ alkoxy, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, carboxy,optionally substituted C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy,optionally substituted C₁₋₆ alkylcarbonyl, formyl, amino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino,mono- and di(C₁₋₆-alkyl)aminocarbonylamino, carbamoyl, mono-anddi(C₁₋₆-alkyl)aminocarbonyl, mercapto, optionally substitutedC₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, cyano, halogen, aryl, aryloxy, arylamino,arylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocycylcarbonyl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl,where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxyl, C₁₋₆-alkoxy, amino, mono and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆ alkylaminocarbonyl or halogen(s)and wherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted;

and R^(N) not being a prodrug group being selected from hydrogen,optionally substituted C₁₋₆-alkyl, hydroxy, optionally substitutedC₁₋₆-alkoxy, optionally substituted C₁₋₆-alkoxycarbonyl, optionallysubstituted C₁₋₆-alkylcarbonyl, formyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, and C₁₋₆-alkylsulphinyl; whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s);

V¹, V², V³, and V⁴ independently are selected from a carbon atom, anon-quaternary nitrogen atom, an oxygen atom, and a sulfur atom, andwhere V⁴ further may be selected from a bond, so that —V¹—V²—V³—V⁴—together with the atoms to which V¹ and V⁴ are attached form an aromaticor heteroaromatic ring;

R¹, R², R³, and R⁴, when attached to a carbon atom, independently areselected from hydrogen, optionally substituted C₁₋₆-alkyl, optionallysubstituted C₂₋₆-alkenyl, hydroxy, optionally substituted C₁₋₆-alkoxy,optionally substituted C₂₋₆-alkenyloxy, carboxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl,optionally substituted C₁₋₆-alkylcarbonyloxy, formyl, amino, mono- anddi(C₁₋₆-alkyl)amino, carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino, cyano, carbamido,mono- and di(C₁₋₆-alkyl)aminocarbonylamino, C₁₋₆-alkanoyloxy,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl,heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heteroaryl,heteroaryloxy, heteroarylamino, heteroarylcarbonyl, and halogen, whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s), andwherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted;

R¹, R², R³, and R⁴, when attached to a nitrogen atom, independently areselected from hydrogen, optionally substituted C₁₋₆-alkyl, hydroxy,optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino,mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl,aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy,heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy,heteroarylcarbonyl, and heteroarylamino; where any C₁₋₆-alkyl as anamino substituent is optionally substituted with hydroxy, C₁₋₆-alkoxy,amino, mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted;

or R¹ and R² together with the carbon atoms to which they are attachedform a ring, e.g. an aromatic ring, a carbocyclic ring, a heterocyclicring or a heteroaromatic ring, in particular an aromatic ring, aheterocyclic ring or a heteroaromatic ring;

with the proviso that when each of V¹, V², V³ and V⁴ represents a carbonatom, then R^(N), R¹, R², R³, and R⁴ are not all hydrogen; and

pharmaceutically acceptable salts thereof.

In this embodiment, at least one of X¹ and X² is preferably a prodruggroup of any of the types (ia) and (iiia)

wherein A is selected from optionally substituted C₁₋₆-alkylidene andoptionally substituted benzylidene,

—C(═O)—B—R⁵ represent an optionally N-substituted amino acid;

R⁶ is selected from hydrogen(glycine), methyl(alanine),2-propyl(valine), 2-methyl-1-propyl(leucine), 2-butyl(isoleucine),methylthioethyl(methionine), benzyl(phenylalanine),3-indolylmethyl(tryptophan), hydroxymethyl(serine),1-hydroxyethyl(threonine), mercaptomethyl(cysteine),4-hydroxybenzyl(tyrosine), aminocarbonylmethyl(asparagine),2-aminocarbonylethyl(glutamine), carboxymethyl(aspartic acid),2-carboxyethyl(glutamic acid), 4-amino-1-butyl(lysine),3-guanidino-1-propyl(arginine), and 4-imidazolylmethyl(histidine), or R⁶and R⁸ together with the intervening carbon and nitrogen atoms to whichthey are attached form a pyrrolidine ring (proline);

R⁷ and R⁸ are independently selected from hydrogen, optionallysubstituted C₁₋₆-alkyl, hydroxy, optionally substituted C₁₋₆-alkoxy,optionally substituted C₁₋₆-alkoxycarbonyl, optionally substitutedC₁₋₆-alkylcarbonyl, formyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino, C₁₋₆-alkylcarbonylamino, mono- and di(C₁₋₆-alkyl)amino,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aryl, aryloxy, arylcarbonyl,arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl,heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, andheteroarylamino; where any C₁₋₆-alkyl as an amino substituent isoptionally substituted with hydroxy, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted; or R⁷ and R⁸together with the nitrogen atoms to which they are attached form aheterocyclic ring.

Moreover, R^(N) may (as the sole prodrug group or in combination withanother prodrug group as X¹ and/or X²) represents a prodrug group of thetype (vii)

wherein A is selected from optionally substituted C₁₋₆-alkylidene andoptionally substituted benzylidene, and —C(═O)—B—R⁵ represent anoptionally N-substituted amino acid.

The further specifications and indications of preferred meanings for thesubstituents X¹, X², R^(N), V¹, V², V³, V⁴, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,and R⁸ given in connection with compound of general formula (I) alsoapply for the compounds of general formula (Ia), mutatis mutandis.

The Compounds of General Formula (Ib)

It has also been found that compounds comprising other particularprodrug groups represents a further particularly interesting aspect ofthe present invention. Hence, the present invention also provides acompound of the general formula (Ib)

wherein

each of X¹ and X² independently represents a prodrug group of any of thetypes (ix)-(x)

(ix) —O—C(═O)—Z, wherein Z is selected from optionally substitutedC₁₋₆-alkenyl and —N(R⁷)R⁸; and

(x) —O—CH₂—C(═O)—Y, wherein Y is selected from optionally substitutedC₁₋₆-alkyl;

-   -   wherein R⁷ and R⁸ are independently selected from hydrogen,        optionally substituted C₁₋₆-alkyl, hydroxy, optionally        substituted C₁₋₆-alkoxy, optionally substituted        C₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl,        formyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino,        C₁₋₆-alkylcarbonylamino, mono- and di(C₁₋₆-alkyl)amino,        C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aryl, aryloxy,        arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy,        heterocyclylcarbonyl, heterocyclylamino, heteroaryl,        heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where        any C₁₋₆-alkyl as an amino substituent is optionally substituted        with hydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino,        carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or        halogen(s), and wherein any aryl, heterocyclyl and heteroaryl        may be optionally substituted, or R⁷ and R⁸ together with the        nitrogen atoms to which they are attached form an optionally        substituted heterocyclic ring;

or is selected from hydrogen, hydroxy, optionally substituted C₁₋₆alkoxy, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, carboxy, optionally substituted C₁₋₆-alkoxycarbonyl,C₁₋₆-alkylcarbonyloxy, optionally substituted C₁₋₆alkylcarbonyl, formyl,amino, mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylsulphonylamino, mono- and di(C₁₋₆-alkyl)aminocarbonylamino,carbamoyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, mercapto, optionallysubstituted C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, cyano, halogen, aryl, aryloxy, arylamino,arylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocycylcarbonyl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl,where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxyl, C₁₋₆-alkoxy, amino, mono and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆ alkylaminocarbonyl or halogen(s)and wherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted;

R^(N) represents a prodrug group of any of the types (xi)-(xii)

(xi) -A-C(═O)—B—R⁵ ; and

(xii) —(CH₂—CH₂—O)₁₋₁₀—R⁵,

-   -   wherein A is selected from optionally substituted        C₁₋₆-alkylidene and optionally substituted benzylidene,    -   B is selected from a single bond, —O— and —S—, and    -   R⁵ is selected from hydrogen, optionally substituted C₁₋₆-alkyl,        optionally substituted C₁₋₆-alkoxy, optionally substituted        C₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl,        mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino,        C₁₋₆-alkylcarbonylamino, mono- and di(C₁₋₆-alkyl)amino, aryl,        aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy,        heterocyclylcarbonyl, heterocyclylamino, heteroaryl,        heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where        any C₁₋₆-alkyl as an amino substituent is optionally substituted        with hydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino,        carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or        halogen(s), and wherein any aryl, heterocyclyl and heteroaryl        may be optionally substituted; or —C(═O)—B—R⁵ in prodrug        group (xi) may represent an optionally N-substituted amino acid;

or is selected from hydrogen, optionally substituted C₁₋₆-alkyl,hydroxy, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino,mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, andC₁₋₆-alkylsulphinyl; where any C₁₋₆-alkyl as an amino substituent isoptionally substituted with hydroxy, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s);

with the proviso that the compound comprises at least one of the prodruggroups (ix)-(xii);

V¹, V², V³, and V⁴ independently are selected from a carbon atom, anon-quaternary nitrogen atom, an oxygen atom, and a sulfur atom, andwhere V⁴ further may be selected from a bond, so that —V¹—V²—V³—V⁴—together with the atoms to which V¹ and V⁴ are attached form an aromaticor heteroaromatic ring;

R¹, R², R³, and R⁴, when attached to a carbon atom, independently areselected from hydrogen, optionally substituted C₁₋₆-alkyl, optionallysubstituted C₂₋₆-alkenyl, hydroxy, optionally substituted C₁₋₆-alkoxy,optionally substituted C₂₋₆-alkenyloxy, carboxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl,optionally substituted C₁₋₆-alkylcarbonyloxy, formyl, amino, mono- anddi(C₁₋₆-alkyl)amino, carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino, cyano, carbamido,mono- and di(C₁₋₆-alkyl)aminocarbonylamino, C₁₋₆-alkanoyloxy,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl,heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heteroaryl,heteroaryloxy, heteroarylamino, heteroarylcarbonyl, and halogen, whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s), andwherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted;

R¹, R², R³, and R⁴, when attached to a nitrogen atom, independently areselected from hydrogen, optionally substituted C₁₋₆-alkyl, hydroxy,optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino,mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl,aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy,heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy,heteroarylcarbonyl, and heteroarylamino; where any C₁₋₆-alkyl as anamino substituent is optionally substituted with hydroxy, C₁₋₆-alkoxy,amino, mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted;

or R¹ and R² together with the carbon atoms to which they are attachedform a ring, e.g. an aromatic ring, a carbocyclic ring, a heterocyclicring or a heteroaromatic ring, in particular an aromatic ring, aheterocyclic ring or a heteroaromatic ring;

with the proviso that when each of V¹, V², V³ and V⁴ represents a carbonatom, then R^(N), R¹, R², R³, and R⁴ are not all hydrogen; and

pharmaceutically acceptable salts thereof.

In one variant, at least one of X¹ and X² represents a prodrug group(ix) —O—C(═O)—Z.

In another variant, at least one of, wherein X¹ and X² represents aprodrug group (x) —O—CH₂—C(═O)—Y.

In a further variant, R^(N) represents a prodrug group (xi)-A-C(═O)—B—R⁵.

In a still further variant, R^(N) represents a prodrug group (xii)—(CH₂—CH₂—O)₁₋₁₀—R⁵.

The further specifications and indications of preferred meanings for thesubstituents X¹, X², R^(N), V¹, V², V³, V⁴, R¹, R², R³, R⁴, R⁵, R⁷, andR⁸ given in connection with compound of general formula (I) also applyfor the compounds of general formula (Ib), mutatis mutandis.

Currently Most Preferred Compounds

Presently very interesting compounds of the formulae (I) and (Ia) and(Ib) are those listed in the following:

(2S)-4-(6,7-difluoro-3-(4-methoxyphenyl)-2-oxoindolin-3-yl)phenyl2-aminopropanoate hydrochloride,

(2S,2′S)-4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-aminopropanoatedihydrochloride,

4,4═-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-aminoacetate)ditrifluoroaceticacid salt,

(2S,2′S)-4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(3-methyl-2-(methylamino)butanoate)dihydrochloride,

4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-dimethylamino)acetate),

(2S)-4-(6,7-difluoro-3-(4-methoxyphenyl)-2-oxoindolin-3-yl)phenyl2-aminophenylpropanoate hydrochloride,

4-(3-(4-chlorophenyl)-6,7-difuoro-2-oxoindolin-3-yl)phenyl(2-morpholinoethoxy)methylcarbonate,

(7-fluoro-3,3-bis(4-hydroxyphenyl)-6-methyl-2-oxoindolin-1-yl)methyl2-morpholinoethyl carbonate,

(4,4′-(6-fluoro-7-methyl-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(oxy)bis(methylene)bis(2-morpholinoethyl)dicarbonate, and

4-(3-(4-chlorophenyl)-6,7-dimethyl-2-oxoindolin-3-yl)phenyl methylmethylphosphonate

Presently very interesting compounds of the formula (Ib) are thoselisted in the following:

6,7-Difluoro-3-(4-fluorophenyl)-1-(2-hydroxyethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one,

4-[6,7-Difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenyl3-morpholinopropanoate,

4-[6,7-Difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenyl3-(4-methylpiperazino)propanoate,

[3-(4-{[(Isopropoxycarbonyl)oxy]methoxy}phenyl)-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methylisopropyl carbonate,

Benzyl2-[3-{4-[2-(benzyloxy)-2-oxoethoxy]phenyl}-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,

4-(3-{4-[(Anilinocarbonyl)oxy]phenyl}-6,7-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl)phenylN-phenylcarbamate,

4-[6,7-Difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenylN,N-dimethylcarbamate,

4-[6-Fluoro-3-(4-fluorophenyl)-7-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]phenylN,N-dimethylcarbamate, and

4-[6-Fluoro-3-(4-fluorophenyl)-7-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]phenylacrylate.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsoutline below and in the Examples section, together with methods knownin the art of organic synthetic organic chemistry, or variations thereofas appreciated by those skilled in the art. Preferred methods include,but are not limited to, those described below.

The novel compounds of formulae (I) and (Ia) and (Ib) may be preparedusing the reactions and techniques described in this section. Thereactions are performed in solvents appropriate to the reagents andmaterials employed and suitable for the transformations being effected.Also, in the synthetic methods described below, it is to be understoodthat all proposed reaction conditions, including choice of solvent,reaction atmosphere, reaction temperature duration of experiment andwork-up procedures, are chosen to be conditions of standard for thatreaction, which should be readily recognized by one skilled in the art.It is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the educt molecule must becompatible with the reagents and reactions proposed. Not all moleculesof formulae (I) and (Ia) and (Ib) falling into a given class may becompatible with some of the reaction conditions required in some of themethods described. Such restrictions to the substituents which arecompatible with the reaction conditions will be readily apparent to oneskilled in the art and alternative methods can be used.

Compounds according to the present invention in which X¹ and/or X² is anamino acid ester may be prepared from compounds of general formula (II)or (III) by coupling with a protected amino acid and subsequent removalof the protecting groups, if any, to yield compounds of general formula(IV) and (V). The condensation is carried out using any of the manymethods for the formation of ester bonds known to one skilled in the artof organic synthesis. These methods include, but are not limited to, useof standard coupling procedures such as use of symmetric carbonicanhydrides, mixed carbonic anhydride (e.g. isobutyl chloroformate)method, carbodiimides (e.g. N,N-dimethylaminopropyl-N′-ethylcarbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide),active ester (e.g. pentaflurophenyl ester, p-nitrophenyl ester,N-hydroxysuccinic imido ester) method, carbonyldiimidazole method, azidemethod, phosphorous reagents such as BOP-Cl, conversion of the protectedamino acid derivative into an acid chloride. Some of these methods(especially carbodiimide) can be enhanced by addition of e.g.1-hydroxybenzotriazole or N,N-dimethylaminopyridine.

Protection groups as referred to above are well known per se, forexample from the techniques of peptide chemistry. Amino groups can oftenbe protected by tert-butyloxycarbonyl, benzyloxycarbonyl or acetylgroups, or in the form of a phtalimido group. Hydroxy groups are oftenprotected as readily cleavable ethers such as the t-butyl or benzylether, or as readily cleavable esters such as the acetate. Carboxylicacid groups are often protected as readily cleavable esters such as thet-butyl or benzyl ester. Thiols are often protected as readily cleavableethers such as the trityl ether.

If R⁷ and R⁸ are both alkyl groups compounds of general formula (IV) and(V) can be converted into the corresponding trialkylammonium salts (VI)and (VII), e.g. by reaction with an alkyl halide and a base or methylmethane sulfonate.

Compounds according to the present invention in which X₁ and/or X₂ is aphosphonate group or a phosphinate group (VIII) and (IX) may be preparedfrom compounds of general formula (II) or (III) e.g. by condensationwith a phosphonochloridate or a phosphinic chloride in the presence of abase.

Compounds according to the present invention in which X¹ and/or X₂ is—O-A-O(C═O)—B—R⁵ (X) and (XI) can be prepared form compounds of general(II) and (III), in which R^(N) is an amide protecting group (e.g. asilyl-type or benzyl type protecting group) by reaction with a base andchloromethyl or iodomethyl esters of general formula (XII), andsubsequent removal of the amide protecting group (e.g. by use offluoride ion or hydrogenation). The chloromethyl or iodomethyl esters ofgeneral formula (XII) may be prepared as described in Bioorg. Med. Chem.Lett. (2005) 13 2491-2494.

Alternatively, compounds of general formula (X) and (XI) may prepared bysimilar methods to those described in Bioorg. Med. Chem. Lett. (2003)1695-1698 after suitable protection of the amide group and subsequentremoval of the protecting group, as described above.

Compounds according to the present invention in which R^(N) is—O-A-O(C═O)—B—R⁵, X¹ and/or X₂ is —O-A-O(C═O)—B—R⁵ (X) and (XI) can beprepared form compounds of general (II) and (III) by reaction with abase of the right choice and chloromethyl or iodomethyl esters ofgeneral formula (XII).

Compounds according to the present invention in which R^(N) is—O-A-O(C═O)—B—R⁵, X₁ and/or X₂ is hydrogen (XII) and (XIII) can beprepared form compounds of general (II) and (III) reaction with a baseof the right choice, e.g. NaH, and chloromethyl or iodomethyl esters ofgeneral formula (XII). The phenolic group(s) may require protectionprior to derivatization of the amide function, e.g. with a Boc-group, asilyl ether or an acyl group, followed by deprotection as the last step.

Compounds according to the present invention in which X¹ and/or X₂ isO-A-O(C═O)—B—R⁵ (XIV) and (XV) can be prepared form compounds of general(II) and (III) by reaction with chloromethyl carbonochloridate and abase, e.g. potassium carbonate or cesium carbonate, and subsequentreaction of the resulting chloromethyl phenylcarbonate with an alcoholor a thiol and a base. Compounds according to the present invention inwhich R^(N) as well as X₁ and/or X₂ is —O—CO—CH₂—OR (XIV) and (XV) canbe prepared form compounds of general (II) and (III) can be prepared asdescribed above with a different choice of base, e.g. NaH.

Compounds according to the present invention in which R^(N) isO-A-O(C═O)—B—R⁵ (XVI) and (XVII) can be prepared form compounds ofgeneral (II) and (III) by protection of the phenolic function(s), e.g.with a Boc-group, a silyl ether or an acyl group, reaction withchloromethyl carbonochloridate and a base, e.g. NaH, and subsequentreaction of the resulting chloromethyl3,3-bis(phenyl)-2-oxoindoline-1-carboxylate with an alcohol or a thiol.and a base, followed by removal of the protecting group(s).

Medical Uses

The compounds of the general formulae (I) and (Ia) and (Ib) are believedto be particularly useful in the treatment of cancer. The term cancer istypically describing cell growth not under strict control. In oneembodiment of the invention, treatment of cancers in which inhibition ofprotein synthesis and/or inhibition of activation of the mTOR pathway isan effective method for reducing cell growth. Examples of such cancersare breast cancer, renal cancer, multiple myeloma, leukemia, glioblastoma, rhabdomyosarcoma, prostate, soft tissue sarcoma, colorectalsarcoma, gastric carcinoma, head and neck squamous cell carcinoma,uterine, cervical, melanoma, lymphoma, and pancreatic cancer.

Hence, the present invention generally provides a compound of thegeneral formula (I) or (Ia) or (Ib) as defined herein for use as amedicament; more particular, the use of a compound of the generalformula (I) or (Ia) or (Ib) as defined herein for the preparation of amedicament for the treatment of cancer in a mammal. Such medicaments mayfurther comprise one or more other chemotherapeutic agents.

Moreover, the present invention provides a method of treating a mammalsuffering from or being susceptible to cancer, the method comprisingadministering to the mammal a therapeutically effective amount of acompound of the general formula (I) or (Ia) or (Ib) as defined herein.

Formulation of Pharmaceutical Compositions

The compounds of the general formulae (I) and (Ia) and (Ib) are suitablyformulated in a pharmaceutical composition so as to suit the desirableroute of administration.

The administration route of the compounds may be any suitable routewhich leads to a concentration in the blood or tissue corresponding to atherapeutic effective concentration. Thus, e.g., the followingadministration routes may be applicable although the invention is notlimited thereto: the oral route, the parenteral route, the cutaneousroute, the nasal route, the rectal route, the vaginal route and theocular route. It should be clear to a person skilled in the art that theadministration route is dependent on the particular compound inquestion; particularly the choice of administration route depends on thephysico-chemical properties of the compound together with the age andweight of the patient and on the particular disease or condition and theseverity of the same.

The compounds may be contained in any appropriate amount in apharmaceutical composition, and are generally contained in an amount ofabout 1-95%, e.g. 1-10%, by weight of the total weight of thecomposition. The composition may be presented in a dosage form which issuitable for the oral, parenteral, rectal, cutaneous, nasal, vaginaland/or ocular administration route.

Thus, the composition may be in form of, e.g., tablets, capsules, pills,powders, granulates, suspensions, emulsions, solutions, gels includinghydrogels, pastes, ointments, creams, plasters, drenches, deliverydevices, suppositories, enemas, injectables, implants, sprays, aerosolsand in other suitable form.

The pharmaceutical compositions may be formulated according toconventional pharmaceutical practice, see, e.g., “Remington'sPharmaceutical Sciences” and “Encyclopedia of PharmaceuticalTechnology”, edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker,Inc., New York, 1988. Typically, the compounds defined herein areformulated with (at least) a pharmaceutically acceptable carrier orexcipient. Pharmaceutically acceptable carriers or excipients are thoseknown by the person skilled in the art. Formation of suitable salts ofthe compounds of the Formulae (I) and (Ia) and (Ib) will also be evidentin view of the before-mentioned.

Thus, the present invention provides in a further aspect apharmaceutical composition comprising a compound of the general Formula(I) or (Ia) or (Ib) in combination with a pharmaceutically acceptablecarrier.

Pharmaceutical compositions according to the present invention may beformulated to release the active compound substantially immediately uponadministration or at any substantially predetermined time or time periodafter administration. The latter type of compositions is generally knownas controlled release formulations.

In the present context, the term “controlled release formulation”embraces i) formulations which create a substantially constantconcentration of the drug within the body over an extended period oftime, ii) formulations which after a predetermined lag time create asubstantially constant concentration of the drug within the body over anextended period of time, iii) formulations which sustain drug actionduring a predetermined time period by maintaining a relatively,constant, effective drug level in the body with concomitant minimizationof undesirable side effects associated with fluctuations in the plasmalevel of the active drug substance (saw-tooth kinetic pattern), iv)formulations which attempt to localize drug action by, e.g., spatialplacement of a controlled release composition adjacent to or in thediseased tissue or organ, v) formulations which attempt to target drugaction by using carriers or chemical derivatives to deliver the drug toa particular target cell type.

Controlled release formulations may also be denoted “sustained release”,“prolonged release”, “programmed release”, “time release”,“rate-controlled” and/or “targeted release” formulations.

Controlled release pharmaceutical compositions may be presented in anysuitable dosage forms, especially in dosage forms intended for oral,parenteral, cutaneous nasal, rectal, vaginal and/or ocularadministration. Examples include single or multiple unit tablet orcapsule compositions, oil solutions, suspensions, emulsions,microcapsules, microspheres, nanoparticles, liposomes, delivery devicessuch as those intended for oral, parenteral, cutaneous, nasal, vaginalor ocular use.

Preparation of solid dosage forms for oral use, controlled release oraldosage forms, fluid liquid compositions, parenteral compositions,controlled release parenteral compositions, rectal compositions, nasalcompositions, percutaneous and topical compositions, controlled releasepercutaneous and topical compositions, and compositions foradministration to the eye will be well-known to those skilled in the artof pharmaceutical formulation. Specific formulations can be found in“Remington's Pharmaceutical Sciences”.

Capsules, tablets and pills etc. may contain for example the followingcompounds: microcrystalline cellulose, gum or gelatin as binders; starchor lactose as excipients; stearates as lubricants; various sweetening orflavouring agents. For capsules the dosage unit may contain a liquidcarrier like fatty oils. Likewise coatings of sugar or enteric agentsmay be part of the dosage unit. The pharmaceutical compositions may alsobe emulsions of the compound(s) and a lipid forming a micellularemulsion.

For parenteral, subcutaneous, intradermal or topical administration thepharmaceutical composition may include a sterile diluent, buffers,regulators of tonicity and antibacterials. The active compound may beprepared with carriers that protect against degradation or immediateelimination from the body, including implants or microcapsules withcontrolled release properties. For intravenous administration thepreferred carriers are physiological saline or phosphate bufferedsaline.

Dosages

In one embodiment, the pharmaceutical composition is in unit dosageform. In such embodiments, each unit dosage form typically comprises0.1-500 mg, such as 0.1-200 mg, e.g. 0.1-100 mg, of the compound.

More generally, the compound are preferably administered in an amount ofabout 0.1-250 mg per kg body weight per day, such as about 0.5-100 mgper kg body weight per day.

For compositions adapted for oral administration for systemic use, thedosage is normally 0.5 mg to 1 g per dose administered 1-4 times dailyfor 1 week to 12 months depending on the disease to be treated.

The dosage for oral administration of the composition in order toprevent diseases or conditions is normally 1 mg to 100 mg per kg bodyweight per day. The dosage may be administered once or twice daily for aperiod starting 1 week before the exposure to the disease until 4 weeksafter the exposure.

For compositions adapted for rectal use for preventing diseases, asomewhat higher amount of the compound is usually preferred, i.e. fromapproximately 1 mg to 100 mg per kg body weight per day.

For parenteral administration, a dose of about 0.1 mg to about 100 mgper kg body weight per day is convenient. For intravenousadministration, a dose of about 0.1 mg to about 20 mg per kg body weightper day administered for 1 day to 3 months is convenient. Forintraarticular administration, a dose of about 0.1 mg to about 50 mg perkg body weight per day is usually preferable. For parenteraladministration in general, a solution in an aqueous medium of 0.5-2% ormore of the active ingredients may be employed.

For topical administration on the skin, a dose of about 1 mg to about 5g administered 1-10 times daily for 1 week to 12 months is usuallypreferable.

Combination Treatment

In an intriguing embodiment of the present invention, the compound ofthe general formula (I) or (Ia) or (Ib) is used therapeutically incombination with one or more other chemotherapeutic agents. Examples ofsuch chemotherapeutic agents are those selected from daunorubicin,docetaxel, prednisone, dexamethasone, decadron, altretamine, amifostine,aminoglutethimide, dactinomycin, anastrozole, asparaginase,bicalutamide, bleomycin, busulfan, carboplatin, carmustine,chlorambucil, chlorodeoxyadenosine, cisplatin, cytosine arabinoside,dacarbazine, doxorubicin, epirubicin, estramustine, diethylstilbestrol,fludarabine, flutamide, 5-fluorouracil, gemcitabine, goserelin,idarubicin, irinotecan, levamisole, lomustine, mechlorathamine, alkeran,mercaptopurine, taxol (e.g. paclitaxel). In particular, the furtherchemotherapeutic agent is selected from taxanes such as Taxol,Paclitaxel and Docetaxel.

Thus, with respect to the use and the method of treatment definedherein, the medicament may further comprise one or more otherchemotherapeutic agents.

With respect to the pharmaceutical composition defined herein, such acomposition may further comprise one or more other chemotherapeuticagents.

Examples

For nuclear magnetic resonance ¹H NMR spectra (300 MHz) and ¹³C NMR(75.6) chemical shift values (δ) (in ppm) are quoted, unless otherwisespecified, for deuteriochloroform solutions relative totetramethylsilane (δ=0.0) or chloroform (δ=7.25) or deuteriochloroform(δ=76.81 for ¹³C NMR) standards. The value of a multiplet, eitherdefined (dublet (d), triplet (t) quartet (q)) or not (m) at heapproximate mid point is given unless a range is quoted. (bs) indicatesa broad singlet. The organic solvents used were anhydrous.

The following abbreviations have been used throughout:

BOC tert-butyloxycarbonyl

DCM dichloromethane

DIC diisoproylcarbodiimide

DMAP dimethylaminopryridine

DMF N,N-dimethylformamide

EDC N-(dimethylaminopropyl)-N′-ethylcarbodiimide

EtOAc ethyl acetate

NMR nuclear magnetic resonance

rt room temperature

TFA trifluoro acetic acid

TLC thin layer chromatography

Starting materials can be prepared as described in the literature, e.g.in WO 2005/097107.

General Procedure 1: Formation of BOC-Protected Amino Acid EsterDerivatives from Phenols of General Formula (II).

The BOC-protected amino acid (12.0 mmol) was dissolved in DCM (20 mL),cooled in an ice bath under argon and DIC (6.0 mmol) was added drop-wisewith stirring. After 1½ h the mixture was filtered, concentrated,redissolved in pyridine (10 mL) and the phenol of general formula (II)(2.0 mmol) was added with stirring. The mixture was stirred at roomtemperature overnight, concentrated three times with toluene. Theresidue was purified by chromatography (1% methanol in DCM) orcrystallization to afford BOC-protected amino acid ester derivativesfrom phenols of general formula (II).

General Procedure 2: Formation of BOC-Protected Amino Acid EsterDerivatives from Phenols of General Formula (III).

The phenol of general formula (III) (0.42 mmol) and the BOC-protectedamino acid (0.59 mmol) were dissolved in DCM, EDC (0.71 mmol) and DMAP(10 mg) were added with stirring and the mixture was left at roomtemperature overnight, transferred to a separatory funnel with EtOAc/H₂Oand shaken. The aqueous phase was extracted twice more with EtOAc. Thecombined organic layers were washed with brine, dried (MgSO₄) andconcentrated. The residue was purified by chromatography (1% methanol inDCM or mixtures of petroleum ether and EtOAc) to afford BOC-protectedamino acid ester derivatives from phenols of general formula (III).

General Procedure 3: Removal of BOC-Protecting Group from BOC-ProtectedAmino Acid Ester Derivatives of Phenols of General Formula (II) orGeneral Formula (III) Using HCl to Yield Compounds of General Formula(IV) or (V).

The BOC-protected amino acid ester derivative of phenol of generalformula (II) or (III)) was dissolved in DCM or methanol and HCl indiethyl ether (1 M) was added. When TLC showed no remaining startingmaterial the mixture was concentrated and if necessary purified bycrystallization to afford compounds of general formula (IV) or (V).

General Procedure 4: Removal of BOC-Protecting Group from BOC-ProtectedAmino Acid Ester Derivatives of Phenols of General Formula (II) orGeneral Formula (III) Using TFA to Yield Compounds of General Formula(IV) or (V).

The BOC-protected amino acid ester derivative of phenol of generalformula (II) or (III)) was dissolved in TFA. After 30 minutes themixture was concentrated twice with toluene and if necessary purified bycrystallization to afford compounds of general formula (IV) or (V).

General Procedure 5: Formation of N,N-Dimethylamino AcidEsterderivatives from Phenols of General Formula (II) or (III).

The phenol of general formula (II) or (III) (0.27 mmol) and theN,N-dimethylamino acid (0.78 mmol) were dissolved in DMF, EDC (0.88mmol) and DMAP (0.27 mmol) were added with stirring. The mixture wasstirred at room temperature overnight, concentrated, extracted withEtOAc/H₂O. The aqueous layer was back-extracted twice with EtOAc, andthe combined organic layers were washed with brine, dried (MgSO₄) andconcentrated. The residue was purified by crystallization to affordcompound of general formula (IV) or (V).

Preparation 1:(2S)-4-(6,7-difluoro-3-(4-methoxyphenyl)-2-oxoindolin-3-yl)phenyl2-(tert-butoxycarbonylamino)propanoate (Compound 1)

General procedure 2. Starting materials:6,7-difluoro-3-(4-hydroxy-phenyl)-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-oneand N-BOC-L-alanine. ¹H-NMR (CDCl₃) δ 8.95 (bs, 1H), 7.27 (d, 2H), 7.13(d, 2H), 7.03 (d, 2H), 6.95-6.75 (m, 4H), 5.17 (d, 1H), 4.56 (q, 1H),3.80 (s, 3H), 1.53 (d, 3H), 1.45 (s, 9H).

Preparation 2:(2S)-4-(6,7-difluoro-3-(4-methoxyphenyl)-2-oxoindolin-3-yl)phenyl2-(tert-butoxycarbonylamino)3-phenylpropanoate (Compound 2)

General procedure 2. Starting materials:6,7-difluoro-3-(4-hydroxy-phenyl)-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-oneand N-BOC-L-phenylalanine.¹H-NMR (CDCl₃) δ 8.60 (bs, 1H), 7.40-7.15 (m,9H), 7.0-6.80 (m 6H), 5.09 (d, 1H), 4.82 (q, 1H), 3.80 (s, 3H), 3.23 (d,2H), 1.46 (s, 9H).

Preparation 3: (2S)-4-(6,7-difluoro-2-oxo-3-p-tolylindolin-3-yl )phenyl2-(tert-butoxycarbonylamino)3-phenylpropanoate (Compound 3)

General procedure 2. Starting materials:6,7-difluoro-3-(4-hydroxy-phenyl)-3-p-tolyl-1,3-dihydro-indol-2-one andN-BOC-L-phenylalanine. ¹H-NMR (CDCl₃) δ 7.78 (bs, 1H), 7.30-7.35 (m,15H) 4.97 (d, 1H), 4.71 (q, 1H), 3.14 (d, 2H), 2.25( s, 3H), 1.36 (s,9H).

Preparation 4: (2S, 2′S)4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-(tert-butoxycarbonylamino)3-propanoate(Compound 4)

General procedure 1. Starting materials:6,7-difluoro-3,3-bis(4-hydroxyphenyl)-indol-2-one and N-BOC-L-alanine.¹H-NMR (CDCl3) δ 9.17 (bs, 1H), 7.17 (d, 4H) 6.97 (d, 4H), 6.85-6.70 (m,2H), 5.07 (d, 2H), 4.46 (q, 2H), 1.45 (s, 6H), 1.38 (s, 18H).

Preparation 5: (2S,2′S)4,4′-(6.7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-(tert-butoxycarbonylamino)acetate (Compound 5)

General procedure 1. Starting materials:6,7-difluoro-3,3-bis(4-hydroxyphenyl)-indol-2-one and N-BOC-glycine.¹H-NMR (CDCl3) δ 8.27 (bs, 1H), 7.17 (d, 4H) 6.97 (d, 4H), 6.88-6.73 (m,2H), 5.01 (bs, 2H), 4.10 (d, 4H), 1.39 (s, 18H).

Preparation 6:(2S,2′S)4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-(tert-butoxycarbonyl(methyl)amino)3-methylbutanoate(Compound 6)

General procedure 1. Starting materials:6,7-difluoro-3,3-bis(4-hydroxyphenyl)-indol-2-one andN-BOC-N-methyl-L-valine. ¹H-NMR (CDCl3) δ 8.15 (bs, 1H), 7.18 (d, 4H)6.96 (d, 4H), 6.87-6.69 (m, 2H), 4.37 (dd, 2H), 2.84 (d, 3H), 2.21 (m,2H), 1.41 (s, 18H), 1.02 (d, 6H), 0.89 (d, 6H).

Example 1(2S)-4-(6,7-difluoro-3-(4-methoxyphenyl)-2-oxoindolin-3-yl)phenyl2-aminopropanoate hydrochloride (Compound 1001)

General procedure 3. Starting materials: compound 1. ¹H-NMR (DMSO-d₆) δ11.59 (s, 1H), 8.59 (bs, 3H), 7.4-6.8 (m, 10H), 4.40 (bs. 1H) 3.73 (s,3H), 1.56 (bs, 3H).

Example 2(2S,2′S)-4,4′-(6,7-difluoro-2-oxoindoline-3.3-diyl)bis(4,1-phenylene)bis(2-aminopropanoatedihydrochloride (Compound 1002)

General procedure 3. Starting materials: compound 4. ¹H-NMR (DMSO-d₆) δ11.70 (s, 1H), 8.69 (bs, 6H), 7.4-6.8 (m, 10H), 4.39 (bs. 2H), 1.55 (bs,6H).

Example 34,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-aminoacetate)ditrifluoroaceticacid salt (Compound 1003)

General procedure 4. Starting materials: compound 5. ¹H-NMR (DMSO-d₆) δ11.70 (s, 1H), 8.43 (bs, 6H), 7.34-7.04 (m, 10H), 4.13 (S, 4H).

Example 4(2S,2′S)-4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(3-methyl-2-(methylamino)butanoate)dihydrochloride(Compound 1004)

General procedure 3. Starting materials: compound 6. ¹H-NMR (DMSO-d₆) δ11.71 (s, 1H), 9.55 (bs, 4H), 7.4-7.0 (m, 10H), 4.26 (bs. 2H), 2.66 (s,6H), 2.48 (m, 2H), 1.17 (d, 6H); 1.05 (d, 6H).

Example 5 4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-dimethylamino)acetate) (Compound 1005)

General procedure 5. Starting materials:6,7-difluoro-3,3-bis(4-hydroxyphenyl)-indol-2-one andN.N-dimethylglycine. ¹H-NMR (DMSO-d₆) δ 11.66 (s, 1H), 7.3-7.0 (m, 10H),3.46 (s, 2H), 2.32 (s, 6H).

Example 6(2S)-4-(6,7-difluoro-3-(4-methoxyphenyl)-2-oxoindolin-3-yl)phenyl2-aminophenylpropanoate hydrochloride (Compound 1006)

General procedure 3. Starting materials: compound 2.¹H-NMR (DMSO-d₆) δ11.57 (s, 1H), 8.71, 7.28-7.42 (m, 5H), 7.17 (d, 2H), 7.0-7.15 (m, 4H),6.86-6.98 (m, 4H), 4.58 (t, 1H), 3.73 (s, 3H), 3.17 (d, 2H)

General Procedure for the Following Examples

¹H NMR spectra were recorded at ambient temperature with Mercury 200(Varian) spectrometer. The HPLC measurements were performed on anAlliance 2695 Separations Module equipped with a Waters 2487 UV detectorby LiChrospher RP Select B 4.0×250 mm column. Elemental analyses wereobtained with a Carlo Erba EA 11 08 instrument. Melting points weremeasured on a “Boetius” micro melting point apparatus and areuncorrected. Chromatographical purifications of compounds were performedby column chromatography (CC) on silicagel, 0.035-0.070 mm, (Acros) orby flash chromatography (FC) on a Biotage SP1 system with a Flash 12+Msilicagel column. All the solvents were purified before use by routinetechniques. To isolate reaction products, the solvents were removed byevaporation using a vacuum rotary evaporator, the water bath temperaturenot exceeding 40° C.

Various reagents were purchased from Acros Organics (JanssensPharmaceuticalaan 3A, 2440 Geel, Belgium).

Example 76,7-Difluoro-3-(4-fluorophenyl)-1-(2-hydroxyethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one(Compound 1007)

To a solution of6,7-difluoro-3-(4-fluorophenyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one(compound 7) (0.200g, 0.56 mmol) in dimethylformamide (0.5 mL)successively 60% NaH in mineral oil (0.010 g, 0.25 mmol) and1,3-dioxalan-2-one (0.054 g, 0.62 mmol) were added. The reaction mixturewas stirred at 140° C. for 18 h, cooled, and concentrated in vacuo. Theresidue was purified by CC (15 g of SiO₂) with dichloromethane-ethanol(100:5) as eluent and twice by FC with dichlormethane-ethanol (gradientfrom 100:0 to 80:20) as eluent to give the title compound 1007 (0.070 g,31%) as a foam, m.p. 80-83° C. 1H-NMR (DMSO-d₆, HMDSO) δ: 3.65 (m, 2H);3.93 (m, 2H); 4.94 (t, J=5.4 Hz, 1H); 6.70 (d, J=8.8 Hz, 2H); 6.95 (d,J=8.8 Hz, 2H); 7.03-7.22 (m, 6H); 9.50 (s, 1H). Anal. Calcd forC₂₂H₁₆F₃NO₃.0.5H₂O, %: C, 64.71; H, 4.20; N, 3.43. Found, %: C, 64.76;H, 4.29; N, 3.58.

Example 84-[6,7-Difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenylacrylate (Compound 1008),4-[6,7-Difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenyl3-morpholinopropanoate (Compound 1009) and4-[6,7-Difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenyl3-(4-methylpiperazino)propanoate (Compound 1010)

To a solution of6,7-difluoro-3-(4-fluorophenyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one(compound 7) (0.180g, 0.5 mmol) and triethylamine (0.22 mL, 1.58 mmol)in dichloromethane (5 mL) at −10° C. acryloyl chloride (0.042 mL, 0.52mmol) was added and the resulting mixture was stirred at thistemperature for 3 h. The reaction mixture was supplemented withdichloromethane (45 mL), washed with sat. NaCl solution (4×10 mL), anddried (Na₂SO₄). The solvent was evaporated and the residue was purifiedby FC with a mixture of petroleum ether and ethylacetate-dichloromethane, 1:1 (gradient from 100:0 to 30:70) as eluent togive the title compound 1008 (0.058 g, 27%) as an oil which solidifiedon standing. ¹H-NMR (CDCl₃, HMDSO) δ: 6.01 (dd, J=1.4, 10.2 Hz, 1H);6.30 (dd, J=10.2, 17.2 Hz, 1H); 6.59 (dd, J=1.4, 17.2 Hz, 1H); 6.78-6.93(m, 2H); 6.99 (t, J=8.8 Hz, 2H); 7.09 (d, J=8.6 Hz, 2H); 7.21 (dd,J=5.3, 8.8 Hz, 2H); 7.24 (d, J=8.6 Hz, 2H); 8.62 (s, 1H).

To a solution of4-[6,7-difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenylacrylate (compound 1008) (0.052 g, 0.13 mmol) in dry acetonitrile (3 mL)morpholine (0.012 mL, 0.14 mmol) followed by bismuth(III)trifluoromethanesulfonate (0.0016 g, 0.0024 mmol) were added and thereaction mixture was stirred overnight at room temperature. Theprecipitated solid was filtered, crystallized from acetonitrile, anddried to give the title compound 1009 (0.032 g, 50%) as white crystals,m.p. 174-175° C. 1H-NMR (DMSO-d₆, HMDSO) δ: 2.33-2.46 (m, 4H, overlappedwith DMSO); 2.57-2.87 (m, 4H, overlapped with DMSO); 3.50-3.62 (m, 4H);6.97-7.26 (m, 10H); ˜11-12 (b s, 1H). Anal. Calcd for C₂₇H₂₃F₃N₂O₄.0.5H₂O.0, %: C, 64.15; H, 4.79; N, 5.54. Found, %: C, 64.04; H, 4.43; N,5.69.

Compound 1010 was prepared from4-[6,7-difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenylacrylate (compound 1008) and 1-methylpiperazine in the same manner asfor compound 1009 above in 61% yield was prepared. M.p. 149-151° C.1H-NMR (DMSO-d₆, HMDSO) δ: 2.13 (s, 3H); 2.30 (m, 4H); 2.40 (m, 4H);2.68 (m, 4H); 6.97-7.27 (m, 10H); 11.61 (b s, 1H). Anal. Calcd forC₂₈H₂₆F₃N₃O₃, %: C, 66.00; H, 5.14; N, 8.25. Found, %: C, 65.82; H,4.96; N, 8.42.

Example 9[3-(4-{[(Isopropoxycarbonyl)oxy]methoxy}phenyl)-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methylisopropyl carbonate (Compound 1011)

To a suspension of3-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one(compound 8) (0.16 g, 0.48 mmol) in water (2.5 mL) K₂CO₃ (0.21 g, 1.5mmol) was added and the mixture was stirred at r.t. for 5 min. ThenBu₄NHSO₄ (0.17 g, 0.5 mmol), dichloromethane (2.5 mL), and iodomethylisopropyl carbonate (0.16 g, 0.65 mmol) were added and the resultingmixture was vigorously stirred at r.t. for 24 h. (The preparation ofiodomethyl isopropyl carbonate was described in literature (Thomas, J.D.; Sloan, K. B. Tetrah. Lett. 2007, 48 (1), 109-112).) The aqueouslayer was separated, the organic layer was supplemented withdichloromethane (10 mL), washed with sat. NaCl solution, and dried(Na₂SO₄). The solvent was evaporated and the residue was purified by CC(20 g of SiO₂) with dichloromethane-ethanol (100:1) as eluent to givethe title compound compound 1011 (0.030 g, 11%) and compound 10 (0.11 g,51%). Compound 1011: m.p. 47-49° C. 1H-NMR (DMSO-d₆, HMDSO) δ: 1.20 (d,J=6.2 Hz, 6H); 1.21 (d, J=6.2 Hz, 6H); 3.72 (s, 3H); 4.79 (septet, J=6.2Hz, 1H); 4.79 (septet, J=6.2 Hz, 1H); 5.76 (s, 2H); 5.83 (s, 2H); 6.89(d, J=8.8 Hz, 2H); 7.02 (d, J=9.0 Hz, 2H); 7.05 (d, J=8.8 Hz, 2H); 7.09(d, J=9.0 Hz, 2H); 7.11-7.22 (m, 1H); 7.25-7.45 (m, 3H). Anal. Calcd forC₃₁H₃₃NO₉, %: C, 66.06; H, 5.90; N, 2.49. Found, %: C, 66.16; H, 5.87;N, 2.51. Compound 9: m.p. 63-65° C. 1H-NMR (DMSO-d₆, HMDSO) δ: 1.21 (d,J=6.2 Hz, 6H); 3.71 (s, 3H); 4.79 (septet, J=6.2 Hz, 1H); 5.75 (s, 2H);6.88 (d, J=8.9 Hz, 2H); 6.91-7.15 (m, 8H); 7.16-7.29 (m, 2H); 10.71 (s,1H). Anal. Calcd for C₂₆H₂₅NO₆, %: C, 69.79; H, 5.63; N, 3.13. Found, %:C, 69.68; H, 5.60; N, 3.13.

Example 10 Benzyl2-[3-{4-[2-(benzyloxy)-2-oxoethoxy]phenyl}-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate(Compound 1012)

Compound 10 and compound 1012 were prepared from3-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one(compound 8) and benzyl 2-bromoacetate by the same protocol as forcompound 1011 above in 15% and 78% yields, accordingly. Compound 10:m.p. 76-78° C. 1H-NMR (DMSO-d₆, HMDSO) δ: 3.72 (s, 3H); 4.83 (s, 2H);5.17 (s, 2H); 6.87 (d, J=8.9 Hz, 2H); 6.87 (d, J=8.9 Hz, 2H); 6.90-7.02(m, 2H); 7.04 (d, J=8.9 Hz, 2H); 7.05 (d, J=8.9 Hz, 2H); 7.16-7.28 (m,2H); 7.33 (s, 5H); 10.69 (s, 1H). Anal. Calcd for C₃₀H₂₅NO₅, %: C,75.14; H, 5.25; N, 2.92. Found, %: C, 74.84; H, 5.32; N, 2.83. Compound1012: m.p. 57-58° C. 1H-NMR (CDCl₃, HMDSO) δ: 3.75 (s, 3H); 4.56 (s,2H); 4.60 (s, 2H); 5.17 (s, 2H); 5.21 (s, 2H); 6.69-6.80 (m, 5H);7.03-7.39 (m, 17H). Anal. Calcd for C₃₉H₃₃NO₇, %: C, 74.63; H, 5.30; N,2.23. Found, %: C, 74.48; H, 5.30; N, 2.19.

Example 114-(3-{4-[(Anilinocarbonyl)oxy]phenyl}-6,7-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl)phenylN-phenylcarbamate (Compound 1013)

To a suspension of6,7-difluoro-3,3-bis(4-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one (0.35g, 1.0 mmol) in dry toluene under argon atmosphere phenyl isocyanate(0.24 mL, 2.2 mmol) was added and the mixture was stirred at reflux for3 h. The precipitated solid was filtered, purified by CC (30 g of SiO₂)with dichloromethane-ethanol (100:1) as eluent and crystallized fromacetonitrile to give the title compound 1013 (0.40 g, 68%), m.p.163-165° C. 1H-NMR (DMSO-d₆, HMDSO) δ: 6.94-7.38 (m, 2H); 7.04 (t, J=7.2Hz, 2H); 7.23 (s, 8H); 7.32 (t, J=7.8 Hz, 4H); 7.49 (d, J=8.0 Hz, 4H);10.25 (br s, 2H); 11.67 (br s, 1H). Anal. Calcd for C₃₄H₂₃F₂N₃O₅.0.7H₂O, %: C, 67.59; H, 4.07; N, 6.95. Found, %: C, 67.61; H, 3.87; N,7.30.

Example 124-[6,7-Difluoro-3-(4-fluorophenyl)-2-oxo-2.3-dihydro-1H-indol-3-yl]phenylN,N-dimethylcarbamate (Compound 1014)

To a solution of6,7-difluoro-3-(4-fluorophenyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one(compound 7) (0.110 g, 0.31 mmol), TEA (0.13 mL, 0.93 mmol), and DMAP(0.0076 g, 0.062 mmol) in THF (7 mL) was added dimethylcarbamyl chloride(0.033 mL, 0.34 mmol) and the reaction mixture was refluxed for 3 h. Thesolvent was evaporated, the residue was dissolved in CH₂Cl₂ (40 mL),washed with sat. NaCl solution (2×10 mL), and dried (Na₂SO₄). Thesolvent was evaporated and the residue was purified by FC withCHCl₃—MeOH (gradient from 100:0 to 80:20) as eluent to give the titlecompound 1014 (0.053 g, 40%) as a white solid, m.p. 98-100° C. ¹H-NMR(DMSO-d₆, HMDSO) δ: 3.00 (s, 3H); 3.08 (s, 3H); 6.77-7.12 (m, 6H);7.14-7.25 (m, 4H); 8.22 (s, 1H). Anal. Calcd for C₂₃H₁₇F₃N₂O₃ as if itcontained 5.⁵% of ballast impurities, %: C, 61.22; H, 3.80; N, 6.21.Found, %: C, 61.25; H, 3.80; N, 6.07.

Example 134-[6-Fluoro-3-(4-fluorophenyl)-7-methyl-2-oxo-2.3-dihydro-1H-indol-3-yl]phenylN,N-dimethylcarbamate (Compound 1015) and4-[6-Fluoro-3-(4-fluorophenyl)-7-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]phenylacrylate (Compound 1016)

Compound 1015 was prepared from6-fluoro-3-(4-fluorophenyl)-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-indol-2-one(compound 11) in the same manner as for compound 1014 above in 60%yield. M.p. 263-265° C. ¹H-NMR (DMSO-d₆, HMDSO) δ: 2.19 (d, J=1.4 Hz,3H); 2.89 (s, 3H); 3.01 (s, 1H); 6.82 (dd, J=8.4, 10.2 Hz, 1H);7.03-7.23 (m, 9H); 11.08 (s, 1H).

To a solution of6-fluoro-3-(4-fluorophenyl)-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-indol-2-one(compound 11) (0.200g, 0.6 mmol) and triethylamine (0.24 mL, 1.7 mmol)in dichloromethane (5 mL) at ice bath temperature acryloyl chloride(0.046 mL, 0.60 mmol) was added and the resulting mixture was stirred atr.t. overnight. The reaction mixture was supplemented withdichloromethane (55 mL), washed with sat. NaCl solution (2 ×10 mL), anddried (Na₂SO₄). The solvent was evaporated and the residue was purifiedby FC with a mixture of petroleum ether and ethylacetate-dichloromethane, 1:1 (gradient from 100:0 to 30:70) as eluent togive the title compound 1016 (0.15 g, 62%) as a white solid, m.p.223-225° C. ¹H-NMR (CDCl₃, HMDSO) δ: 2.20 (d, J=1.3 Hz, 3H); 6.15 (dd,J=2.2, 9.5 Hz, 1H); 6.39 (dd, J=9.5, 17.2 Hz, 1H); 6.52 (dd, J=2.2, 17.2Hz, 1H); 6.83 (dd, J=8.3, 10.2 Hz, 1H); 7.08-7.28 (m, 9H); 11.11 (s,1H).

1. A compound of the general formula (I)

wherein each of X¹ and X² independently represents a prodrug group ofany of the types (i)-(vi) (i) —O—C(═O)—Z, wherein Z is selected fromsubstituted C₁₋₆-alkyl and —CH(R⁶)N(R⁷)R⁸; (ii) —O—C(═O)—O—Y, wherein Yis selected from optionally substituted C₁₋₆-alkyl, or —O—Y represents

wherein A is selected from optionally substituted C₁₋₆-alkylidene andoptionally substituted benzylidene, B is selected from a single bond,—O— and —S—, R⁵ is selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono-and di(C₁₋₆-alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino,heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino,heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino;where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, orhalogen(s), and wherein any aryl, heterocyclyl and heteroaryl may beoptionally substituted; or —C(═O)—B—R⁵ in prodrug groups (iii) and (vii)may represent an optionally N-substituted amino acid; R⁶ is selectedfrom hydrogen, optionally substituted C₁₋₆-alkyl, optionally substitutedC₂₋₆-alkenyl, aryl, heterocyclyl, and heteroaryl, wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted, or R⁶ and R⁸together with the intervening carbon and nitrogen atoms to which theyare attached form a heterocyclic ring; R⁷ and R⁸ are independentlyselected from hydrogen, optionally substituted C₁₋₆-alkyl, hydroxy,optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino,mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl,aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy,heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy,heteroarylcarbonyl, and heteroarylamino; where any C₁₋₆-alkyl as anamino substituent is optionally substituted with hydroxy, C₁₋₆-alkoxy,amino, mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted, or R⁷ and R⁸together with the nitrogen atoms to which they are attached form aheterocyclic ring; and R⁹ is selected from hydrogen, hydroxy, optionallysubstituted C₁₋₆-alkyl, optionally substituted C₁₋₆-alkoxy, andoptionally substituted C₂₋₆-alkenyloxy; R¹⁰ is selected from hydroxy,optionally substituted C₁₋₆-alkyl, optionally substituted C₁₋₆-alkoxy,optionally substituted C₂₋₆-alkenyloxy; aryloxy, heterocyclyloxy, andheteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may beoptionally substituted; provided that R⁹ and R¹⁰ are not both selectedfrom hydroxy and C₁₋₆-alkoxy; or is selected from hydrogen, hydroxy,optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, carboxy, optionally substitutedC₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy, optionally substituted C₁₋₆alkylcarbonyl, formyl, amino, mono- and di(C₁₋₆-alkyl)amino,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino, mono- anddi(C₁₋₆-alkyl)aminocarbonylamino, carbamoyl, mono-anddi(C₁₋₆-alkyl)aminocarbonyl, mercapto, optionally substitutedC₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, cyano, halogen, aryl, aryloxy, arylamino,arylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocycylcarbonyl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl,where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxyl, C₁₋₆-alkoxy, amino, mono and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆ alkylaminocarbonyl or halogen(s)and wherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted; R^(N) represents a prodrug group of any of the types(vii)-(viii)

wherein A, B and R⁵ are as defined above for prodrug group (iii); or isselected from hydrogen, optionally substituted C₁₋₆-alkyl, hydroxy,optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino,mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, andC₁₋₆-alkylsulphinyl; where any C₁₋₆-alkyl as an amino substituent isoptionally substituted with hydroxy, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s); with the proviso that thecompound comprises at least one of the prodrug groups (i)-(viii); V¹,V², V³, and V⁴ independently are selected from a carbon atom, anon-quaternary nitrogen atom, an oxygen atom, and a sulfur atom, andwhere V⁴ further may be selected from a bond, so that —V¹—V²—V³—V⁴—together with the atoms to which V¹ and V⁴ are attached form an aromaticor heteroaromatic ring; R¹, R², R³, and R⁴, when attached to a carbonatom, independently are selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, hydroxy, optionallysubstituted C₁₋₆-alkoxy, optionally substituted C₂₋₆-alkenyloxy,carboxy, optionally substituted C₁₋₆-alkoxycarbonyl, optionallysubstituted C₁₋₆-alkylcarbonyl, optionally substitutedC₁₋₆-alkylcarbonyloxy, formyl, amino, mono- and di(C₁₋₆-alkyl)amino,carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino, cyano, carbamido,mono- and di(C₁₋₆-alkyl)aminocarbonylamino, C₁₋₆-alkanoyloxy,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl,heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heteroaryl,heteroaryloxy, heteroarylamino, heteroarylcarbonyl, and halogen, whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s), andwherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted; R¹, R², R³, and R⁴, when attached to a nitrogen atom,independently are selected from hydrogen, optionally substitutedC₁₋₆-alkyl, hydroxy, optionally substituted C₁₋₆-alkoxy, optionallysubstituted C₁₋₆-alkoxycarbonyl, optionally substitutedC₁₋₆-alkylcarbonyl, formyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino, C₁₋₆-alkylcarbonylamino, mono- and di(C₁₋₆-alkyl)amino,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aryl, aryloxy, arylcarbonyl,arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl,heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, andheteroarylamino; where any C₁₋₆-alkyl as an amino substituent isoptionally substituted with hydroxy, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted; or R¹ and R²together with the carbon atoms to which they are attached form a ring;with the proviso that when each of V¹, V², V³ and V⁴ represents a carbonatom, then R^(N), R¹, R², R³, and R⁴ are not all hydrogen; andpharmaceutically acceptable salts thereof.
 2. The compound according toclaim 1, wherein at least one of X¹ and X² represents a prodrug group(i) —O—C(═O)—Z. 3-5. (canceled)
 6. The compound according to claim 1,wherein at least one of X¹ and X² represents a prodrug group (ii)—O—C(═O)—O—Y.
 7. (canceled)
 8. The compound according to claim 1,wherein at least one of X¹ and X² represents a prodrug group (iii)

9-11. (canceled)
 12. The compound according to claim 1, wherein at leastone of X¹ and X² represents a prodrug group of any of the types(iv)-(vi)

13-14. (canceled)
 15. The compound according to claim 1, wherein R^(N)represents a prodrug group or any of the types (vii)-(viii)

16-17. (canceled)
 18. The compound according to claim 1, wherein each ofV¹, V², V³, and V⁴ represents a carbon atom.
 19. The compound accordingto claim 1, wherein R¹, R², R³ and R⁴ are not all hydrogen. 20-22.(canceled)
 23. The compound according to claim 1, wherein R^(N) ishydrogen.
 24. The compound according to claim 1, wherein each of V¹, V²,V³, and V⁴ represents a carbon atom; R¹ and R² are both fluoro; R³ andR⁴ are all hydrogen; R^(N) is hydrogen; at least one of X¹ and X²represents a prodrug group (i) —O—C(═O)—CH(R⁶)—N(R⁷)R⁸, wherein R⁶ isselected from hydrogen(glycine), methyl(alanine), 2-propyl(valine),2-methyl-1-propyl(leucine), 2-butyl(isoleucine),methylthioethyl(methionine), benzyl(phenylalanine),3-indolylmethyl(tryptophan), hydroxymethyl(serine),1-hydroxyethyl(threonine), mercaptomethyl(cysteine),4-hydroxybenzyl(tyrosine), aminocarbonylmethyl(asparagine),2-aminocarbonylethyl(glutamine), carboxymethyl(aspartic acid),2-carboxyethyl(glutamic acid), 4-amino-1-butyl(lysine),3-guanidino-1-propyl(arginine), and 4-imidazolylmethyl(histidine), or R⁶and R⁸ together with the intervening carbon and nitrogen atoms to whichthey are attached form a pyrrolidine ring (proline); R⁷ is hydrogen andR⁸ is selected from hydrogen, optionally substituted C₁₋₆-alkyl,optionally substituted C₁₋₆-alkoxycarbonyl, optionally substitutedC₁₋₆-alkylcarbonyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aryl, arylcarbonyl,heterocyclyl, heterocyclyloxy, heteroaryl, and heteroaryloxy; where anyC₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s), andwherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted; or R⁷ and R⁸ together with the nitrogen atoms to which theyare attached form a heterocyclic ring; and any other of X¹ or X² isselected from hydrogen, hydroxy, optionally substituted C₁₋₆ alkoxy,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,carboxy, optionally substituted C₁₋₆-alkoxycarbonyl,C₁₋₆-alkylcarbonyloxy, optionally substituted C₁₋₆ alkylcarbonyl,formyl, amino, mono- and di(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylsulphonylamino, mono- and di(C₁₋₆-alkyl)aminocarbonylamino,carbamoyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, mercapto, optionallysubstituted C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, cyano, halogen, aryl, aryloxy, arylamino,arylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocycylcarbonyl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl,where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxyl, C₁₋₆-alkoxy, amino, mono and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆ alkylaminocarbonyl or halogen(s)and wherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted.
 25. A compound of the general formula (Ia)

wherein at least one of X¹, X² and R^(N) represent a prodrug groupcomprising an amino acid moiety, any of X¹ and X² not being a prodruggroup independently being selected from hydrogen, hydroxy, optionallysubstituted C₁₋₆ alkoxy, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, carboxy, optionally substitutedC₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy, optionally substituted C₁₋₆alkylcarbonyl, formyl, amino, mono- and di(C₁₋₆-alkyl)amino,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino, mono- anddi(C₁₋₆-alkyl)-aminocarbonylamino, carbamoyl, mono-anddi(C₁₋₆-alkyl)aminocarbonyl, mercapto, optionally substitutedC₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, cyano, halogen, aryl, aryloxy, arylamino,arylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocycylcarbonyl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl,where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxyl, C₁₋₆-alkoxy, amino, mono and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆ alkylaminocarbonyl or halogen(s)and wherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted; and R^(N) not being a prodrug group being selected fromhydrogen, optionally substituted C₁₋₆-alkyl, hydroxy, optionallysubstituted C₁₋₆-alkoxy, optionally substituted C₁₋₆-alkoxycarbonyl,optionally substituted C₁₋₆-alkylcarbonyl, formyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, and C₁₋₆-alkylsulphinyl; whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s); V¹, V²,V³, and V⁴ independently are selected from a carbon atom, anon-quaternary nitrogen atom, an oxygen atom, and a sulfur atom, andwhere V⁴ further may be selected from a bond, so that —V¹—V²—V³—V⁴—together with the atoms to which V¹ and V⁴ are attached form an aromaticor heteroaromatic ring; R¹, R², R³, and R⁴, when attached to a carbonatom, independently are selected from hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, hydroxy, optionallysubstituted C₁₋₆-alkoxy, optionally substituted C₂₋₆-alkenyloxy,carboxy, optionally substituted C₁₋₆-alkoxycarbonyl, optionallysubstituted C₁₋₆-alkylcarbonyl, optionally substitutedC₁₋₆-alkylcarbonyloxy, formyl, amino, mono- and di(C₁₋₆-alkyl)amino,carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino, cyano, carbamido,mono- and di(C₁₋₆-alkyl)aminocarbonylamino, C₁₋₆-alkanoyloxy,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl,heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heteroaryl,heteroaryloxy, heteroarylamino, heteroarylcarbonyl, and halogen, whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s), andwherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted; R¹, R², R³, and R⁴, when attached to a nitrogen atom,independently are selected from hydrogen, optionally substitutedC₁₋₆-alkyl, hydroxy, optionally substituted C₁₋₆-alkoxy, optionallysubstituted C₁₋₆-alkoxycarbonyl, optionally substitutedC₁₋₆-alkylcarbonyl, formyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino, C₁₋₆-alkylcarbonylamino, mono- and di(C₁₋₆-alkyl)amino,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aryl, aryloxy, arylcarbonyl,arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl,heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, andheteroarylamino; where any C₁₋₆-alkyl as an amino substituent isoptionally substituted with hydroxy, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted; or R¹ and R²together with the carbon atoms to which they are attached form a ring;with the proviso that when each of V¹, V², V³ and V⁴ represents a carbonatom, then R^(N), R¹, R², R³, and R⁴ are not all hydrogen; andpharmaceutically acceptable salts thereof. 26-27. (canceled)
 28. Acompound selected from the group consisting of(2S)-4-(6,7-difluoro-3-(4-methoxyphenyl)-2-oxoindolin-3-yl)phenyl2-aminopropanoate hydrochloride,(2S,2′S)-4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-aminopropanoatedihydrochloride,4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-aminoacetate)ditrifluoroaceticacid salt,(2S,2′S)-4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(3-methyl-2-(methylamino)butanoate)dihydrochloride,4,4′-(6,7-difluoro-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(2-dimethylamino)acetate),(2S)-4-(6,7-difluoro-3-(4-methoxyphenyl)-2-oxoindolin-3-yl)phenyl2-aminophenylpropanoate hydrochloride,4-(3-(4-chlorophenyl)-6,7-difuoro-2-oxoindolin-3-yl)phenyl(2-morpholinoethoxy)methylcarbonate,(7-fluoro-3,3-bis(4-hydroxyphenyl)-6-methyl-2-oxoindolin-1-yl)methyl2-morpholinoethyl carbonate,(4,4′-(6-fluoro-7-methyl-2-oxoindoline-3,3-diyl)bis(4,1-phenylene)bis(oxy)bis(methylene)bis(2-morpholinoethyl)dicarbonate, and4-(3-(4-chlorophenyl)-6,7-dimethyl-2-oxoindolin-3-yl)phenyl methylmethylphosphonate.
 29. A compound of the general formula (Ib)

wherein each of X¹ and X² independently represents a prodrug group ofany of the types (ix)-(x) (ix) —O—C(═O)—Z, wherein Z is selected fromoptionally substituted C₁₋₆-alkenyl and —N(R⁷)R⁸; and (x)—O—CH₂—C(═O)—Y, wherein Y is selected from optionally substitutedC₁₋₆-alkyl; wherein R⁷ and R⁸ are independently selected from hydrogen,optionally substituted C₁₋₆-alkyl, hydroxy, optionally substitutedC₁₋₆-alkoxy, optionally substituted C₁₋₆-alkoxycarbonyl, optionallysubstituted C₁₋₆-alkylcarbonyl, formyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aryl,aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy,heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy,heteroarylcarbonyl, and heteroarylamino; where any C₁₋₆-alkyl as anamino substituent is optionally substituted with hydroxy, C₁₋₆-alkoxy,amino, mono- and di(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted, or R⁷ and R⁸together with the nitrogen atoms to which they are attached form anoptionally substituted heterocyclic ring; or is selected from hydrogen,hydroxy, optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, carboxy, optionallysubstituted C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy, optionallysubstituted C₁₋₆ alkylcarbonyl, formyl, amino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino,mono- and di(C₁₋₆-alkyl)aminocarbonylamino, carbamoyl, mono-anddi(C₁₋₆-alkyl)aminocarbonyl, mercapto, optionally substitutedC₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, cyano, halogen, aryl, aryloxy, arylamino,arylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocycylcarbonyl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl,where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxyl, C₁₋₆-alkoxy, amino, mono and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆ alkylaminocarbonyl or halogen(s)and wherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted; R^(N) represents a prodrug group of any of the types(xi)-(xii) (xi) -A-C(═O)—B—R⁵ ; and (xii) —(CH₂—CH₂—O)₁₋₁₀—R⁵, wherein Ais selected from optionally substituted C₁₋₆-alkylidene and optionallysubstituted benzylidene, B is selected from a single bond, —O— and —S—,and R⁵ is selected from hydrogen, optionally substituted C₁₋₆-alkyl,optionally substituted C₁₋₆-alkoxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, mono-and di(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono-and di(C₁₋₆-alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino,heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino,heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino;where any C₁₋₆-alkyl as an amino substituent is optionally substitutedwith hydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino,carboxy, C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, orhalogen(s), and wherein any aryl, heterocyclyl and heteroaryl may beoptionally substituted; or —C(═O)—B—R⁵ in prodrug group (xi) mayrepresent an optionally N-substituted amino acid; or is selected fromhydrogen, optionally substituted C₁₋₆-alkyl, hydroxy, optionallysubstituted C₁₋₆-alkoxy, optionally substituted C₁₋₆-alkoxycarbonyl,optionally substituted C₁₋₆-alkylcarbonyl, formyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino, C₁₋₆-alkylcarbonylamino, mono- anddi(C₁₋₆-alkyl)amino, C₁₋₆-alkylsulphonyl, and C₁₋₆-alkylsulphinyl; whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s); withthe proviso that the compound comprises at least one of the prodruggroups (ix)-(xii); V¹, V², V³, and V⁴ independently are selected from acarbon atom, a non-quaternary nitrogen atom, an oxygen atom, and asulfur atom, and where V⁴ further may be selected from a bond, so that—V¹—V²—V³—V⁴— together with the atoms to which V¹ and V⁴ are attachedform an aromatic or heteroaromatic ring; R¹, R², R³, and R⁴, whenattached to a carbon atom, independently are selected from hydrogen,optionally substituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl,hydroxy, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₂₋₆-alkenyloxy, carboxy, optionally substituted C₁₋₆-alkoxycarbonyl,optionally substituted C₁₋₆-alkylcarbonyl, optionally substitutedC₁₋₆-alkylcarbonyloxy, formyl, amino, mono- and di(C₁₋₆-alkyl)amino,carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylsulphonylamino, cyano, carbamido,mono- and di(C₁₋₆-alkyl)aminocarbonylamino, C₁₋₆-alkanoyloxy,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aminosulfonyl, mono- anddi(C₁₋₆-alkyl)aminosulfonyl, nitro, optionally substitutedC₁₋₆-alkylthio, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl,heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heteroaryl,heteroaryloxy, heteroarylamino, heteroarylcarbonyl, and halogen, whereany C₁₋₆-alkyl as an amino substituent is optionally substituted withhydroxy, C₁₋₆-alkoxy, amino, mono- and di(C₁₋₆-alkyl)amino, carboxy,C₁₋₆-alkylcarbonylamino, C₁₋₆-alkylaminocarbonyl, or halogen(s), andwherein any aryl, heterocyclyl and heteroaryl may be optionallysubstituted; R¹, R², R³, and R⁴, when attached to a nitrogen atom,independently are selected from hydrogen, optionally substitutedC₁₋₆-alkyl, hydroxy, optionally substituted C₁₋₆-alkoxy, optionallysubstituted C₁₋₆-alkoxycarbonyl, optionally substitutedC₁₋₆-alkylcarbonyl, formyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino, C₁₋₆-alkylcarbonylamino, mono- and di(C₁₋₆-alkyl)amino,C₁₋₆-alkylsulphonyl, C₁₋₆-alkylsulphinyl, aryl, aryloxy, arylcarbonyl,arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl,heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, andheteroarylamino; where any C₁₋₆-alkyl as an amino substituent isoptionally substituted with hydroxy, C₁₋₆-alkoxy, amino, mono- anddi(C₁₋₆-alkyl)amino, carboxy, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl,heterocyclyl and heteroaryl may be optionally substituted; or R¹ and R²together with the carbon atoms to which they are attached form a ring;with the proviso that when each of V¹, V², V³ and V⁴ represents a carbonatom, then R^(N), R¹, R², R³, and R⁴ are not all hydrogen; andpharmaceutically acceptable salts thereof. 30-33. (canceled)
 34. Acompound selected from the group consisting of6,7-Difluoro-3-(4-fluorophenyl)-1-(2-hydroxyethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one,4-[6,7-Difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenyl3-morpholinopropanoate,4-[6,7-Difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenyl3-(4-methylpiperazino)propanoate,[3-(4-{[(Isopropoxycarbonyl)oxy]methoxy}phenyl)-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methylisopropyl carbonate, Benzyl2-[3-{4-[2-(benzyloxy)-2-oxoethoxy]phenyl}-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate,4-(3-{4-[(Anilinocarbonyl)oxy]phenyl}-6,7-difluoro-2-oxo-2,3-dihydro-1H-indol-3-yl)phenylN-phenylcarbamate,4-[6,7-Difluoro-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]phenylN,N-dimethylcarbamate,4-[6-Fluoro-3-(4-fluorophenyl)-7-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]phenylN,N-dimethylcarbamate, and4-[6-Fluoro-3-(4-fluorophenyl)-7-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]phenylacrylate.
 35. A pharmaceutical composition comprising a compound of thegeneral formula (I) as defined in claim 1 and a pharmaceuticallyacceptable carrier. 36-39. (canceled)
 40. A method of treating a mammalsuffering from or being susceptible to cancer, the method comprisingadministering to the mammal a therapeutically effective amount of acompound of the general formula (I) as defined in claim
 1. 41. A methodof treating a mammal suffering from or being susceptible to cancer, themethod comprising administering to the mammal a therapeuticallyeffective amount of a compound of the general formula (Ia) as defined inclaim
 25. 42. A method of treating a mammal suffering from or beingsusceptible to cancer, the method comprising administering to the mammala therapeutically effective amount of a compound of the general formula(Ib) as defined in claim 29.